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pru vrui npiMATir.p RIPHFXVI <; (prRO- ENVIRONMENTAL IMPACT, BIOCHEMICAL AND TOXIC RESPONSES AND IMPLICATIONS FOR RISK ASSESSMENT
5. Safe
Department of Veterinary Physiology and Pharmacology Texas A&M University College Station, Texas 77843-4466 ABSTRACT
Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of isomers and congeners which can be unequivocally identified and quantitated. PCBs elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2.3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons which act through the aryl hydrocarbon (Ah) receptor signal transduction pathway. Structure- activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibit diverse biochemical and toxic responses.
Structure-toxicity studies suggest that the coplanar PCBs, namely 3.3 ',4,4'- tetrachlorobiphenyl (tetraCB), 3,3',4,4'-pentaCB and 3,3',4,4',5,5'-hexaCB and their monoortho analogs are Ah receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds have utilized a toxic equivalency factor (TEF) approach for the hazard and risk assessment of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) congeners in which the TCDD or toxic equivalents (TEQ) of a mixture is related to the
TEQ = £ ( [ PCDF, x TEF, ]„ ) + £ ( [ PCDD, x TEFt ]„ )
TEFs and concentrations of the individual (i) congeners (note: n = the number of congeners). Based on the results of quantitative structure-activity data, the following TEFs are recommended for the coplanar and monoortho coplanar PCBs: 3,3',4,4',5-pentaCB, 0.1;
3,3',4,4',5,5'-hexaCB, 0.05; 3,3',4,4'-tetraCB, 0.02; 2,3,3', 4,4 '-pentaCB, 0.001; 2,3',4,4',5- pentaCB, 0.0001; 2,3,3',4,4',5-hexaCB, 0.0003; 2,3,3',4,4',5'-hexaCB, 0.0003; 2',3,4,4',5- pentaCB. 0.00005; and 2.3.4,4'.5-pentaCB. 0.0002. Application of the TEF approach for the risk assessment of PCBs must be used with considerable caution. Analysis of the results of laboratory animal and wildlife studies suggests that the predictive value of TEQs for PCBs may be both species- and response-dependent since both additive.and non-additive
(antagonistic) interactions have been observed with PCB mixtures. In the latter case, the
TEF approach would significantly overestimate the toxicity of a PCB mixture. Analysis of the rodent carcinogenicity data for Aroclor 1260 using the TEF approach suggests that this response is primarily Ah receptor-independent. Thus, risk assessment of PCB mixtures which uses cancer as an endpoint cannot utilize a TEF approach and requires more quantitative information on the individual congeners which contribute to the tumor promoter activity of PCB mixtures. I. INTRODUCTION
Polychlorinated biphenyls (PCBs) are members of the halogenated aromatic group of environmental pollutants which have been identified worldwide in diverse environmental matrices. PCBs are produced by the chlormation of biphenyl and the resulting products are marketed according to their % chlorine content (by weight)45-142-232-455. For example, Aroclor
1221, 1232. 1242, 1248, 1254 and 1260 are commercial PCBs which were formerly produced by the Monsanto Chemical Company and contain 21, 32, 42, 48, 54 and 60% chlorine (by weight). The last two digits in the numerical designation for the different Aroclors denotes the % chlorine content. Similar commercial PCB mixtures have been produced by other manufacturers and these include the Clophens (Bayer, Germany), Phenoclors and Pyralenes
(Prodelec, France), Fenclors (Caffaro, Italy) and Kanechlors (Kanegafuchi, Japan).
Commercial PCBs have also been manufactured in several other countries including the former U.S.S.R. and Czechoslovakia. The commercial PCBs exhibit a broad range of physicochemical properties which are dependent, in part, on their degree of chlorination and these properties contribute to the diverse applications of PCBs in numerous products. For example, PCBs have been used as organic diluents, pesticide extenders, adhesives, dedusting agents, cutting oils, flame retardants, heat transfer fluids, dielectric fluids for transformers and capacitors, hydraulic lubricants, sealants, and in carbonless copy paper. Some of the uses of PCBs have resulted in the direct introduction of PCBs into the environment; however, a significant portion of the environmental burden of these compounds has resulted
from careless disposal practices, accidents, leakage from various industrial facilities, and
from chemical waste disposal sites. The total amount of PCBs produced worldwide and the
proportion which is present in the environment is unknown; however, it has been estimated 5 that 1.5 million metric tons have been produced worldwide M2.
The chemical properties which are primarily responsible for many of the industrial applications of PCBs, namely their chemical stability and miscibility with organic compounds
(i.e. lipophilicity), are also the same properties which have contributed to their environmental problems. Once introduced into the environment, the relatively stable PCBs resist environmental breakdown and undergo cycling and transport within the various components of the global ecosystem. Moreover, due to the lipophilicity of PCBs, these compounds preferentially bioaccumulate and biomagnify in higher trophic levels of the food chain 2M•M9-459•4*°. The environmental problems and the difficulties encountered in the
hazard and risk assessment of PCBs have also arisen because of another chemical property of these compounds, namely the relatively non-specific chlorination of biphenyl232. This lack of chlorination site specificity means that the commercial PCB products and environmental
PCB residues are complex mixtures of isomers and congeners. Thus, the impacts of PCBs
on the environment and biota are due to the individual components of these mixtures, their additive and/or non-additive (synergistic or antagonist) interactions with themselves and other chemical classes of pollutants. Therefore, the development of scientifically-based
regulations for the risk management of PCBs which would protect against adverse
environmental and human health effects would require analytical and lexicological data on
the individual PCB congeners present in any PCB mixture and information regarding their
interactive effects. There are significant challenges associated with a congener-specific
approach for the analysis and risk assessment of PCBs and these studies are currently
ongoing in several laboratories and regulatory agencies. This review will focus on some of
the more recent studies which have added to our understanding of PCBs and will also 6 discuss problems associated with PCB toxicology and risk assessment which are ongoing and have not yet been resolved.
II. PCBs: ENVIRONMENTAL IMPACT
The development of improved techniques for PCB analysis has played a pivotal role in understanding the environmental fate and potential adverse human health and environmental impacts of PCBs. In the late 1960s, Soren Jensen first detected PCBs in environmental samples as a series of complex peaks which were observed in a gas chromatographic screening of environmental samples for DDT and related compounds 26.
Subsequent studies in several laboratories have identified PCBs in almost every component of the global ecosystem including air, water, sediments, fish, wildlife and human tissues 3I
H. 4M5. 77. ,70. 20,. 2,9. 235. 260. 262. 263. 307. 372.43,. 460, 522. 529-534. 573. 583 j^ Q{ ^ ^ ^^ ^j^ low resolution packed column gas chromatographic separation of the PCB mixtures in which concentrations were determined by matching specific peak patterns and their intensities with the corresponding peaks in commercial PCBs or combinations of different commercial mixtures which were used as standards 57S. The criteria for the selection of commercial PCB standards were variable; however, in many cases, the choice was due to the similarities between the chromatographic peak patterns observed for the standard mixture and the PCBs in the analyte. High resolution analysis for PCB mixtures was first reported by Sissons and
Welti501 and there has been continued improvements in both the resolution capabilities of capillary columns and detection methods 8 '• 47' 263- 369-371 416-457- 48°-5
(w/w) and the congener composition of each PCB mixture was dependent on their chlorine composition 48°. Inspection of the analytical data shows that some congeners occur in only one of the PCB mixtures whereas others are detected in all of the mixtures.
PCBs have been identified as residues from extracts of diverse environmental samples. In all cases, the PCBs are present as complex mixtures of isomers and congeners and, until recently, most routine analytical surveys reported "total PCB" levels using the peak matching technique with commercial Aroclors as standards 575. The PCB levels in extracts are dependent on the nature of the environmental sample and the location. In localized areas with high levels of PCB contamination, there is an increased concentration of PCBs in various environmental extracts. For example, atmospheric PCB levels in an electroindustrial plant in Belakrajina (Yugoslavia) averaged 2000 ^g/m3 and the levels over a PCB-containing waste landfill were 22 to 70 /xg/m3. In contrast, PCB levels 300 m from the factory and in a nearby residential area were 4 to 7 and 2 to 5 /ig/m3, respectively 233.
Moreover, as noted above, PCBs bioconcentrate in higher trophic levels of the food chain and this has been aptly demonstrated within the North American Great Lakes ecosystem.
For example, PCBs were biomagnified 12.9-fold from plankton to fish in a Lake Michigan food web 1M.
Regulatory agencies and environmental scientists have recognized that the composition of PCBs in most environmental extracts does not resemble the composition of the commercial products. Individual PCBs exhibit different physicochemical properties which 8 influence their rates of partitioning, uptake and retention in environmental matrices and their rates of breakdown by various environmental pathways (e.g. photolysis, microbial degradation, and metabolism) 232. The results in Table 1 summarize the congener-specific analysis of Aroclor 1260 and PCBs in human breast milk samples collected from mothers living in the Great Lakes region and the United Kingdom 150'459. The results demonstrate that the PCB composition of the commercial Aroclor differs markedly from the distribution of PCB congeners in extracts from both breast milk samples. For example, some compounds such as 2,4,4',5-tetrachlorobiphenyl are present in relatively high concentrations in human milk (3.7 to 11% of total PCBs) but are a minor component (0.03%) of Aroclor
1260. Other congeners such as 2,2',3,3',4,5,6'-heptaCB and 2,2',3,4,5,5',6-heptaCB are major components of Aroclor 1260 (5.5 and 4.1% of total PCBs, respectively) but are trace components of human milk extracts (< 0.4% to non-detectable for both compounds). The high resolution analytical data also shows significant differences in the composition of the
PCBs obtained from North America or United Kingdom human milk samples and this no doubt reflects differences in composition of the PCBs present in food products from these countries. For example, the combined level of 2,2',5-triCB, 2,2',4-triCB and 4,4'-diCB in the United Kingdom sample was 13.7% whereas these lower chlorinated congeners were not detected in the North American samples. There were some congeners such as 2,2',3,4,4',5'- hexaCB and 2,2',4,4',5,5'-hexaCB which constituted > 10% of the total PCBs in both milk samples and are also major components of Aroclor 1260 (6.5 and 9.6%, respectively). Several high resolution congener-specific analysis of numerous fish and wildlife samples from different parts of the world have also revealed both similarities and differences in the relative concentrations of the PCB congeners. However, in most extracts from biota, the 9 predominant compounds are 2,2',3,4,4',5'-hexaCB, 2,2',4,4',5,5'-hexaCB and 2,2',3,4,4',5,5'-
heptaCB8284'120'*9 (Figure 1).
Three PCB congeners, namely 3,3',4,4'-tetraCB,3,3',4,4'-5-pentaCB and 3,3',4,4',5,5'- hexaCB, elicit toxic responses similar to those reported for 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) and were not routinely detected or quantitated in analytic surveys for PCBs 189.193,4iM2i. 445.450.453.454.458.5*7 However, several recent studies have reported analytical methods for the detection and quantitation of these congeners and several of their
monoortho-substituted analogs in commercial PCBs, environmental samples and in humans
30, 148, ,30. 2,7. 225. 268-27,, 353. 475. 509. 529-535. 537. 579 ^ potemial adverse impacts Qf these n0n.OrthO- coplanar PCBs and their monoortho analogs will be discussed in more detail in Section V of this review. The results in Table 2 illustrate the levels of the coplanar PCBs in human
milk or adipose tissue samples from different locations including upper New York State,
Ontario, Quebec and Japan I4S-217- ™-268'269 353'47$- "'• »'•533'53S "7 579. Again there was
considerable variability in the range of or mean concentrations of these compounds. Fish and wildlife samples taken from different locations also exhibit large differences in the
relative concentrations of the coplanar PCBs. These no doubt reflect the variable
environmental distribution of PCBs which is dependent on several factors including the
magnitude of local and regional inputs, differential rates of environmental breakdown, the
importance of transport processes, and the composition of PCB residues in the food chain
species.
Thus, analysis of environmental samples clearly demonstrates that their PCB
composition is highly variable and does not resemble the composition of the commercial
PCB mixtures. Currently, environmental standards for PCBs are derived from the results 10 of animal studies with commercial PCB mixtures (e.g. Aroclor 1260). However, a meaningful risk assessment of PCBs in food products or environmental samples must take into account the potential adverse impacts of the individual congeners and their concentrations in these samples and should not rely on the toxicity of a known commercial mixture such Aroclor 1260 or Clophen A60. The toxic equivalency factor (TEF) approach which is now being used as an interim measure for the risk assessment of PCDDs and
PCDFs 2"s- "•62> 315> 3Ml 45° and has been discussed as a model for congener-specific risk assessment of PCBs 3> 5 44S0'560. The TEF model for specific structural classes of compounds such as PCBs presupposes a common mechanism of toxic action. Before the potential utility and pitfalls of this model for risk assessment of PCBs can be discussed, the biochemical and toxic effects of PCBs (mixtures and congeners) in humans, laboratory animals and other model systems must be understood.
HI. PCBs: ADVERSE HUMAN HEALTH EFFECTS
The development and validation of a more scientifically-based approach for the risk assessment of PCB congeners requires information on the adverse effects of PCB mixtures on exposed human populations and laboratory animal models. These data coupled with the results of studies on the effects of individual PCB congeners in animal and cell model systems can be utilized to identify specific structural classes of PCBs which may be etiologic agents in PCB-induced adverse effects in humans.
There have been 3 major scenarios in which humans have been exposed to PCB mixtures and these include (i) exposure of workers who produced PCBs or utilized PCB- containing products; (ii) accidental exposure of individuals, and (iii) environmental exposure 11 of populations through contaminated food, air and water. The adverse human health effects
of PCBs on several groups of occupationally-exposed workers have been extensively documented and reviewed 220-282-284'308'447-452-541. PCB exposure in the workplace can result
in exceedingly high body burdens of these compounds and this human population is the most highly exposed group. The reported effects of PCBs on occupationally-exposed humans are variable and dependent on the objectives and design of each study (Table 3). Some of these effects include chloracne and related dermal lesions, diverse hepatic effects including increased serum levels of liver enzymes and lipids, induced hepatic drug metabolizing
enzymes, hepatomegaly, decreased birthweight in the offspring of occupationally-exposed
mothers, decreased pulmonary function, and eye irritation. Worker exposure to PCBs did not affect mortality IOI> 1 and, in some studies, no significant correlations were observed between PCB levels (serum or adipose tissue) and a response. For example, Emmett and coworkers 1S6 16° 16S examined serum and adipose tissue PCB levels in transformer repair workers. It was shown that PCB levels were highest in currently exposed workers, lowest in unexposed workers and intermediate in post-exposed workers. However, there was no significant correlation between PCB levels and symptoms of putative PCB-induced toxicosis. These studies also quantitated the concentrations of several individual PCB congeners in the three different groups and the relative concentrations of the major congeners were similar. The adverse health effects of PCBs on workers exposed at toxic waste sites or during accidents or fires which involved PCB-containing equipment such as transformers or capacitors have also been investigated I71> Ul-394< ils> 519. Although some neurobehavioral dysfunction may have been associated with PCB exposure (firemen)281, there were no correlations between PCB levels 12 and any sign of PCB-induced effects. Fitzgerald and coworkers 171 reported a number of problems reported by firemen; however, these were not directly linked to PCB exposure. Several studies have reported or reviewed the incidence of cancer in workers exposed to PCBs 39'40'70IG1-l02'138'206' "*•493'5". In the cohorts which contained the largest number of workers, the results indicated that no overall increases in cancer-related mortality could be correlated with occupational exposure to PCBs. However, in several of these studies, there are increased incidences of specific cancers including melanomas 39 40 rectal and liver cancer 102, liver gall bladder and biliary tract cancerlot, gastrointestinal tract cancer in males, and hematologic neoplasms 70. Some of the increases in cancer incidences at specific sites were not statistically significant and it was also evident that the carcinogenic effects observed in these workers were different for each study. These results suggest that in the highly exposed worker population, PCBs do not cause a consistent increase in one or more cancers and, therefore, their carcinogenicity in humans has not been established. However, the carcinogenic effects of PCBs in laboratory animals has been amply demonstrated449 493 and, for this reason, continued monitoring of occupationally-exposed workers is warranted. Several thousand individuals were poisoned with PCBs in two separate accidents in Japan and Taiwan when PCB-containing industrial fluid accidentally leaked into rice oil which was subsequently sold to consumers 311-313-436'437 xhe symptomology of victims of the Yusho (Japan) and Yu Cheng (Taiwan) accidents has been extensively investigated and includes severe and persistent chloracne, dark brown pigmentation of nails, distinctive hair follicles,skin thickening, various ocular problems, numbness in some extremities, and numerous subjective complaints which may be associated with neurological problems. In addition, offspring of Yu Cheng mothers were smaller, exhibited learning deficits, and 13 displayed some of the same symptoms observed in their mothers 4J6-437. The rather severe effects caused by the PCB-contaminated rice oil indicated that there were differences in the toxic potency of PCB contaminated rice oil and "normal" industrial PCBs. Many of the acute and chronic effects observed in Yusho and Yu Cheng victims were not observed in the occupationally-exposed population even though serum PCB levels in Yusho/Yu Cheng patients and industrial workers exposed to PCBs were comparable and in many cases higher in the latter group. For example, the PCB serum levels in occupationally-exposed workers can be as high as 100 ppm whereas the mean PCB blood levels of Yu Cheng victims taken a short time after the accident varied from 39 to 101.7 ppb 228, suggesting that chemical contaminants other than PCBs played an important role in the etiology of Yu Cheng/Yusho poisoning. Moreover, the distribution of PCBs in Yusho patients was similar to that observed in other exposed populations 3U. Several papers have reported that the highly toxic polychlorinated dibenzofurans (PCDFs) are present as trace (ppm) impurities in many commercial Japanese and North American PCB preparations 87'88 "9 36M63< 367. PCDFs and other chlorinated aromatic hydrocarbons were subsequently identified in the PCB industrial fluid which contaminated the rice oil in both the Yusho and Yu-Cheng poisonings "9 127 128 3 272.360,362 -j^ ratio of pCDFs/PCBs in the Yu-Cheng and Yusho oils was 2.4 x 10' and 9.0 x 10'3, respectively, whereas the ratio in the commercial PCB, Kanechlor 400, was 3.3 x 10"5 indicating the relatively higher concentration of the PCDFs in the Yusho oil. Moreover, adipose tissue and serum analysis of Yusho/Yu Cheng victims, workers and normal individuals clearly showed that although their PCB levels were comparable, the corresponding PCDF concentrations were consistently higher in the Yusho and Yu Cheng patients m' 31°. Laboratory studies using rodents 4* 31° and different fractions of simulated 14 "rice oil PCBs" (containing the PCDF fraction) or reconstituted PCB and PCDF mixtures which resemble the distribution of these compounds in Yusho patients have demonstrated that the PCDFs were significantly more potent than the PCB fraction. Thus, although PCBs were involved in the Yusho and Yu-Cheng poisonings, the evidence suggests that the major etiologic agents in these incidents were the PCDF contaminants which were present in relatively high concentrations in the industrial fluid which leaked into the rice oil. Based on the moderate adverse human health effects of PCBs on occupationally- exposed workers, it is unlikely that adult exposure to relatively low environmental levels of PCBs would be associated with any adverse health effects. One recent study 166 reported that PCBs levels were significantly elevated in human breast lipids from breast cancer patients. The significance of this correlation and the relationship between organochlorine pollutant exposure levels and human breast cancer has not been established and requires further investigation particularly since some PCBs exhibit antiestrogenic activity 309. Jacobson and coworkers designed a series of studies to examine the developmental effects associated with exposure to environmental contaminants including PCBs by examining the offspring of mothers who consumed Lake Michigan sports fish '**•245'251. Their results showed that there was a correlation between cord serum PCB levels and several parameters such as decreased birth weight and head circumference and neurodevelopmental deficits in infants which included poorer performance on the Brazelton Neonatal Behavioral Assessment Scale, on the psychomotor index of the Bayley Scales of Infant Development and on Pagan's Visual Recognition Memory Test. Rogan, Gladen and their coworkers also showed a correlation between the levels of prenatal PCB exposure of North Carolina infants from the general population and the former two tests for neurodevelopment deficits 182'183 15 438-wo jn a fonow.Up study on the Michigan children at four years of age, the children with the high levels of prenatal exposure to PCBs showed deficits on the McCarthy Scales involving both verbal and numerical memory 249- 25°. In contrast, in the North Carolina children who exhibited neurodevelopmental deficits as infants, no significant correlations were observed between PCB levels and poorer grades on McCarthy scores at three, four, or five years of age 182. In summary, it was shown that prenatal exposure to PCBs correlated with smaller birth weight and memory and learning deficits in infants and young children. In the North Carolina study, these effects were not observed in three to five year old children whereas at four years of age the children in the Michigan group still showed some developmental deficits. The reasons for the differences in the age-dependent outcomes are unclear and require further definition. The structural classes of PCBs which are responsible for the developmental problems are unknown; moreover, it is possible that some other chemicals which were not determined by chemical analysis may contribute to or be responsible for the observed responses. Rogan, Hsu and coworkers have investigated the comparable developmental deficits in infants exposed to PCDFs/PCBs in the Yu Cheng poisoning incident in Taiwan m> 436-437 -598 . Many of the toxic responses observed in the mothers were also seen in the infants and the exposed children exhibited some of the same developmental deficits reported in the low level PCB-exposed children in North Carolina. Although many of the toxic responses noted in the Yu Cheng incident were probably due to the highly toxic PCDFs, the toxins responsible for the developmental deficits may be the PCBs, PCDFs or their combination. The prenatal exposure of the Yu Cheng infants to PCDFs would be significantly higher than the children in the North Carolina study; however, the magnitude 16 of the neurodevelopmental deficits in both groups were similar. This suggests that the highly toxic PCDFs may not be the major etiologic agents associated with this developmental problem. Thus, there may be an association between in utero exposure to PCBs and developmental deficits observed in infants and young children. However, the duration of these adverse effects and the precise identification of the toxic agents are currently unknown and require further study. IV, PCB MIXTURES: TOXIC AND BIOCHEMICAL EFFECTS (a) Toxicity of Commercial Mixtures The toxic and biochemical effects of various commercial PCB mixtures have been extensively investigated in various laboratory animals, fish and wildlife species. Unfortunately, only limited data is available on the toxic effects of other PCB mixtures which resemble environmental PCB residues or of fractionated PCB mixtures. One of the major problems associated with the toxicity of commercial PCBs is related to the relative levels of PCDFs which have been identified as contaminants in several commercial PCB preparations. In most studies, the PCDF content was not determined and their contribution to PCB-induced toxic responses are unknown but in most cases their effects may be relatively minor 4J0. Commercial PCBs elicit a broad spectra of toxic responses which are dependent on several factors including (i) the chlorine content and source of the commercial mixture, (ii) the animal species and strain, (iii) the age and sex of the animal, and (iv) the route and duration of exposure to the commercial mixture. The results in Table 4 summarize many of the toxic responses observed in laboratory animals after exposure to commercial PCBs 17 and these effects include acute lethality, hepatomegaly, fatty liver and other indicators of hepatoxicity, porphyria, body weight loss, dermal toxicity, thymic atrophy, immunosuppressive effects, reproductive and developmental toxicity, carcinogenesis ,other genotoxic responses, modulation of diverse endocrine-derived pathways, and neurotoxicity. The development of PCB-induced toxicity is dependent on a number of factors as noted above; however, the data suggests that the liver is a common target organ and various symptoms of hepatoxicity have been observed in studies with diverse laboratory animal species. Detailed discussions and analysis of PCB-induced toxic responses have previously been reviewed 283.445.449.450.453.454.458,499,597 and ^ nm be fanheT elaborated in this article; however, the effects of various factors on the toxicities mediated by PCB mixtures will be briefly discussed. (i) Species/strain-dependent responses. The dermal toxicity of PCBs has been noted in occupationally-exposed workers220-346-398 and has also been observed in laboratory animals including some strains of mice, rabbits (ears) and monkeys. The PCB-induced dermal toxicities are most pronounced in monkeys and these effects include alopecia, edema, distinctive hair follicles, hair loss, hyperkeratosis and fingernail loss (see Table 4). In contrast, most other laboratory animals are insensitive to PCB-mediated dermal effects and this response pattern is reminiscent of TCDD and related HAHs which act through the aryl hydrocarbon (Ah) receptor >*>.«<>• «>•««. (ii) Sex-dependent effects. Many of the toxic effects caused by PCBs are observed in both males and females; however, some responses can be sex-specific. After chronic administration of Aroclor 1260 to male and female Sprague-Dawley rats, the incidence of hepatocellular adenocarcinomas and trabecular carcinomas were 51 and 40% in female rats 18 and 4 and 0% in male rats, respectively 392. In contrast, the increased incidence of gastric intestinal metaplasia and adenocarcinoma was observed in both male and female F344 rats maintained on diets containing Aroclor 1254571 . Thus the carcinogenic effects of commercial PCBs can be both sex-dependent and -independent depending on the animal species used, the target organ site and possibly the composition of the PCB mixture. (iii) Age-dependent effects. Several studies have shown that there was a correlation between developmental deficits in infants and young children and cord serum PCB levels i6«. U2. IM. 245,2si, 438^40 y^g data suggeste(j tnat prenatal in utero exposure, and not postnatal exposure through breast milk, was important for the impaired development in humans. Comparable results were obtained in rats which were pre- and postnatally exposed to Clophen A30325 326. The PCB mixture caused alterations in active avoidance learning and retention of a visual discrimination task in prenatally-exposed offspring whereas postnatal exposure did not cause any detectable behavioral changes. These data from both human and animal studies were complementary and suggest that the fetus may be more susceptible to PCB-induced neurodevelopmental deficits than infants or older animals. (iv) Structure-dependent toxicities. The commercial PCB mixtures differ with respect their chlorine content and their relative distribution of individual isomers and congeners. A few studies have compared the relative potencies of more than one PCB mixture and the results indicate that there are both structure-dependent and -independent potency differences. Egg production in White Leghorn pullets was decreased in animals maintained on a diet containing Aroclor 1232, 1242, 1248 and 1254 (20 ppm) but no effects were observed for Aroclors 1221 or 1268 327. Moreover, based on other parameters measured in this study, the most toxic mixtures were Aroclors 1242, 1248 and 1254. These 19 data showed that both the high and low chlorinated PCB mixtures exhibited the lowest toxicity. Schaeffer and coworkers 471 utilized male Wistar rats as model for determining the effects of chronic feeding of 100 ppm of Clophen A30 and Clophen A60. After 800 days, the incidence of hepatocellular carcinomas in the Clophen A60, Clophen A30 and control rats was 61, 3 and 2%, respectively. The results of this study illustrated the significant differences between the hepatocarcinogenicity of the more potent higher chlorinated Clophen A60 (60% Cl by weight) versus the lower chlorinated Clophen A30 (42% Cl by weight) PCB mixture. These data, coupled with other studies on PCB-induced carcinogenicity 493 suggest that the higher chlorinated PCB mixtures such as Aroclor 1260 and Clophen A60 were more carcinogenic than lower chlorinated mixtures. This was also observed for PCB-induced immunotoxicity in mice in which the order of potency was Aroclor 1260 > 1254 > 1248 > 1242 > 1016 > 1232 139. In contrast, PCB-induced lethality (Table 4) was not consistently dependent on the degree of chlorination of the commercial PCB. The toxicities of commercial PCBs are due to the individual isomers and congeners in these mixtures and it is possible that one or more structural subclasses of the PCBs contribute to the different toxic responses elicited by PCB mixtures. The identification of these structural subclasses will be discussed in Section V of this review. However, it is clear that there is not a consistent structure-dependent effect of the commercial PCB mixtures for all induced toxicities and this suggests that more than one structural subclass of PCB congeners is responsible for these responses. This conclusion is important for developing schemes for congener-specific hazard and risk assessment of PCBs (see Section VI). (b) Carcinogenicity of Commercial Mixtures Several studies have reported that after a single or repeated administration of 20 commercial PCBs to laboratory rodents they develop an increased incidence of liver lesions including neoplastic nodules and hepatocellular carcinomas. These responses were primarily observed in studies with Aroclor 1260 and Clophen A60 in rats and, in addition, Aroclor 1254 increased the incidence of intestinal metaplasia in F344 rats and this may lead to glandular adenocarcinoma in stomachs of these animals. The evidence for the mutagenicity and genotoxicity of PCBs has been extensively reviewed449-493. PCB mixtures and congeners tend to be non-mutagenic in the Ames test for bacterial mutagenesis and there is only limited data which support the genotoxic action of these mixtures. A recent study383 showed that after multiple administration of high doses of Aroclor 1254 (500 mg/kg) no PCB-DNA adducts were detected in the liver, lung or kidney DNA using the highly sensitive 32P- postlabeling assay. There have been extensive studies on the activities of PCBs as cancer promoters using several different experimental protocols and both long and short term assays which measure the formation of tumors or putative preneoplastic lesions such as nodules or papillomas. The results in Table 5 summarize results of promotion studies with PCB mixtures. In all of these studies, the animals are initiated with a carcinogen followed by repeated or continuous (dietary) administration of the promoter (ie. PCB mixture). The results show that after initiation with a variety of carcinogens, PCBs promote hepatocellular carcinomas and neoplastic nodules in the rat and similar effects were observed in mouse skin and lung. In addition, PCB mixtures also promote the formation of enzyme-altered foci in rats and chickens initiated with different carcinogens. The enzyme-altered foci which are typically characterized in the short term initiation/promotion bioassays for PCBs exhibit decreased ATPase or increased 7-glutamyl transpeptidase (GGT) activities. The results obtained for PCB mixtures are similar to those reported for other tumor promoters 21 including phenobarbital, TCDD and other halogenated aromatic compounds 'y7 261-418-427-451- 479 Aroclor 1254 also inhibited aflatoxin Bl-mediated carcinogenesis in rainbow trout and this was related to altered metabolism and decreased DNA binding by the carcinogen 221 488,489 yjjg effects of PCB mixtures and selected congeners have also been investigated 122 using the resistant hepatocyte model 508. The PCBs used in these studies included Aroclor 1254 and a reconstituted mixture of PCBs, and no initiating activity was observed for these mixtures at the doses used in this study. The antitumor activity of Aroclor 1254 in rats inoculated with Walker 256 carcinosarcoma cells has also been reported 279. Depending on the timing of the treatment with PCBs and the number of tumor cells used in the study, Aroclor 1254 inhibited tumor growth, increased the latency period for tumor development, increased the host survival time and caused tumor regression (if administered after the tumors were established). It has also been reported that Aroclor 1254 did not promote carcinogen-initiated tumors in a two-stage mouse (CD-1) skin tumorigenesis assay 58. In a subsequent study 69, treatment of CD-1 mice with Aroclor 1254 18 hours prior to application of 7,12-dimethylbenzanthracene resulted in decreased papilloma formation (note: TPA was used as a promoter in this experiment). Thus, although the results strongly support the promoting activity of several commercial PCB mixtures, these same mixtures also inhibit carcinogen-induced tumor or preneoplastic cell formation in certain animal models. Smith and coworkers50* have reported a synergistic interaction between Aroclor 1254 and iron in Ah-responsive C57BL/10ScSn mice in the development of hepatocellular carcinomas whereas the toxic effects were significantly lower in Ah non-responsive DBA/2 22 mice. Due to limitation in the number of animals used and toxicity, the role of iron status and the Ah locus requires further investigation. Using this same model system, it was reported that Aroclor 1254 (+ iron overload)-induced carcinomas were not accompanied by H-ras mutations which frequently are observed in hepatomas induced by other carcinogens Ml. The mutations of protooncogenes or tumor suppressor genes and their role in PCB-induced carcinogenesis is unknown and should be further investigated. (c) Biochemical Changes Induced by PCB Mixtures The results in Table 6 summarize the biochemical changes which have been observed in laboratory animals after exposure to PCB mixtures. The induction of hepatic cytochrome P450 and diverse P450-dependent monooxygenases is a sensitive indicator of PCB exposure which has been observed in multiple species including rats IM3-15-l6- " 2'-74 10M06-l53 I76-2t»-209- 91 69 218. 224. 234. 239-244. 266. 317. 334. 335. 378-381. 393, 412. 415. 505. 527, 544. 549. 595 ^ ^ hepatoma cdls in culture ' * ' 470,546.550] ^^ 20. 60. 61. 78. 231, 254, 334. 464) ^^ 21. 4K monkeys 338 fe,.^ 3H ^ 1.8,354.355,432 mink 1U U4, guinea pig us, kestrel 1S8, herring gulls 17S, cockerels 2U, barn owls 429'430, insects 24 and fish ' li6- '"• m-20S-212'223- ™-3i2-382'568. The PCB-induced microsomal enzymes from different species increase the oxidative metabolism of diverse substrates such as benzo[a]pyrene and related polynuclear aromatic hydrocarbons (PAHs), aflatoxin, nitrosamines and other carcinogens, various N- and O-alkyl-substituted compounds (dealkylation), direct hydroxylation and epoxidation of many other xenobiotics and drugs. Inducers of hepatic drug-metabolizing enzyme activities were traditionally divided into two main classes typified by phenobarbital (PB) and 3-methylcholanthrene (MC) 13S 136 507. Pretreatment of rats with PB-type inducers enhances numerous hepatic drug-metabolizing enzyme activities including several cytochrome P-450-dependent monooxygenases (such as 23 dimethylaminoantipyrine (DMAP), ethylmorphine and related /V-dealkylases, biphenyl-4- hydroxylase, aldrin epoxidase and several O-dealkylases including pentoxyresorufin O- dealkylase. In contrast, MC and MC-type inducers enhance hepatic microsomal benzo[a]pyrene hydroxylase (aryl hydrocarbon hydroxylase, AHH), ethoxyresorufin O- deethylase (EROD) and several other cytochrome P450-dependent monooxygenases. The commercial PCBs, typified by Aroclor 1254 induces both MC and PB-inducible monoxygenase and were initially classified as "mixed-type" inducers I6. Subsequent studies in several laboratories have demonstrated that the mixed-type induction pattern observed for PCB mixtures in rodents was due to the induction of both PB (CYP2A1, CYP2B1, CYP2B2)- and MC (CYP2A1, CYP1A1, CYPlA2)-inducible P450 isozymes "•«».«*"«•»'-»». In contrast to rodents, PB does not induce P450 isozymes in fish and only CYP1A1 is induced by PCB mixtures 516. PCBs also induce P450 isozymes which regulate steroid metabolism in some species I79- 18Si 264 and inhibited various adrenal steroid hydroxylases in the guinea pig l84-'86. There are other reports which indicate that commercial PCBs repress the constitutive expression of pulmonary P450 isozymes486 557~559. Borlakoglu and coworkers 79-8I have also reported the induction of lauric acid hydroxylase activity by Aroclor 1254 in both rat and pigeon liver suggesting that PCBs induce CYP4A1. Commercial PCBs induce other enzymes associated with drug-metabolism and these include glutathione S-transferases, epoxide hydrolase and glucuronosyl transferases. Moreover, Table 6 summarizes a host of other biochemical responses induced by various commercial PCBs and these include 6-aminolevulinic acid synthetase (ALAS), c-Ha-ras, c- raf, c-yes, c-erbA and c-erbB protooncogene mRNA levels, various serum lipids and lipoproteins, and HMG-CoA reductase, hepatic lipoperoxidation, fatty acid desaturases, lung 24 pepsinogen isozymes and aldehyde dehydrogenase activities. PCBs also cause a decrease in ALA dehydratase and uroporphyrinogen decarboxylase activities and these responses are associated with development of PCB-induced porphyria. Thus commercial PCBs elicit a large number of toxic and biochemical responses in multiple species and target organs. Since these industrial compounds are complex mixtures, the induced responses must be due to the contributions of individual PCB congeners and their possible non-additive (synergistic or antagonist) responses. Extensive research on the structure-activity relationships (SARs) among various structural classes of PCBs has been carried out in order to identify the individual congeners which are responsible for PCB (mixture)-induced effects. Characterization of the effects of individual PCB congeners and their relative potencies is also important for the development of procedures for the risk and hazard assessment of this class of pollutants since the PCB composition of environmental residues does not resemble that of the commercial products. V. PCB CONGENERS AND DERIVED METABOLITES: STRUCTURE-FUNCTION RELATIONSHIPS (a) Characterization of Ah Receptor Agonists (i) Coplanar PCBs. Structure-induction studies in several laboratories demonstrated that three congeners, namely 3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB and 3,3',4,4',5,5'-hexaCB (Figure 2) resembled TCDD or MC as inducers of CYP1A1 and CYP1A2 gene expression and several associated enzyme activities in a variety of species (Table 7). In addition, 3,4,4',5-tetraCB also exhibited comparable activity 496. These compounds are all substituted in both para and at least two meta positions and the removal 25 of any one of these substituents or the addition of one or more orr/io-chlorine groups results in a significant loss of "MC-type" activity. The data summarized in Table 7 demonstrate that the coplanar PCBs which are present in relatively low concentrations in the commercial Aroclors must contribute to the induction of CYP1A1 by these mixtures. 3,3',4,4',5-PentaCB also suppresses the expression of the constitutive male-specific rat hepatic CYP2C11 59° 59' and there is evidence that both 3,3',4,4',5-pentaCB and 3,3',4,4'-tetraCB induce CYP4A1- dependent activities 79 229. However, the induction of w- and w-1 fatty acid hydroxylase activity (Le. CYP4A1) is not specific for coplanar PCBs since 2,2',4,4',5,5'-hexaCB also induced this response. Coplanar PCBs also induce epoxide hydrolase and glutathione transferase activities and these induction responses were also observed for other structural classes of PCBs (see below). A recent report " suggested than the induction of the glutathione S-transferase P-form (GST-P, 7-7) may be specific for coplanar PCBs. The induction of CYP1A1 gene expression by TCDD, MC and related compounds has been extensively investigated 19V 576~578 and the results are consistent with the role of the Ah receptor in mediating this response. The chemical inducer initially binds to the cytosolic Ah receptor; the resulting receptor complex undergoes transformation, nuclear translocation, and binding to specific genomic sequences (dioxin responsive elements, DREs) prior to the induction of gene transcription. Thus, the liganded Ah receptor complex acts as a nuclear transcriptional enhancer for the induction of CYP1A1 gene expression. The coplanar PCBs competitively bind with relatively high affinity to the cytosolic Ah receptor 49 and this interaction is consistent with the subsequent induction of CYP1A1 gene expression by these congeners. Extensive genetic studies and structure-toxicity relationships with TCDD and related polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) support a 26 role for the Ah receptor in mediating many of the toxic and carcinogenic responses elicited by these compounds 193 420-421 ^ 576-578 Moreover, many of these responses, including the wasting syndrome, thymic atrophy, neurotoxicity, hepatotoxicity and porphyria, reproductive and developmental toxicity, dermal toxicity, immunotoxicity, endocrine effects, decreased vitamin A levels, antiestrogenicity, altered lipid metabolism and carcinogem'city are also observed in animals treated with many of the commercial PCB matures (Tables 4 through 6). The results summarized in Table 7 show that the coplanar PCBs also elicit the same pattern of Ah receptor-mediated responses in diverse species suggesting that this structural class of PCB congeners contributes to the toxicities induced by commercial PCB mixtures. Moreover, the relative potencies of the coplanar PCBs for several responses in genetically inbred mice segregated with their Ah-responsiveness 433-494-495. For example, 3,3',4,4'- tetraCB (100 mg/kg) inhibited the splenic plaque-forming cell (PFC) response to sheep red blood cells (SRBCs) and induced hepatic P450 levels in Ah-responsive C57BL/6 mice whereas at the same dose no effects were observed in the less-responsive DBA/2 mice 495. The differential induction activity of coplanar PCBs was also observed for AHH induction in the genetically inbred C57BL/6 and DBA/2 mice 4". (ii) Monoortho coplanar PCBs. The results of extensive structure-function studies showed that the monoortho coplanar derivatives of the 4 coplanar PCBs (Figure 3) constituted a second major structural class of compounds which exhibited Ah receptor agonist activities. This group of PCBs includes several congeners which have been identified in commercial PCB mixtures and environmental extracts, namely 2,3,3',4,4'-pentaCB, 2,3',4,4',5-pentaCB and 2,3,3',4,4',5-hexaCB. The monoortho coplanar PCBs resemble Aroclor 1254 as inducers of hepatic drug-metabolizing enzyme activities and induce 27 CYP1A1. CYP1A2, CYP2B1, CYP2B2 and CYP2A1 gene expression. Similar results have been obtained for some of the analagous brominated biphenyls 4U 4" 4M. Thus the introduction of a single ortho chloro substituent to the coplanar PCBs did not eliminate the "MC-type" induction pattern but resulted in a series of compounds which exhibited "mixed- type" activity. The monoortho coplanar PCBs also competitively bound to the rat cytosolic Ah receptor 49 and the major difference between the coplanar and monoortho coplanar PCBs as Ah receptor ligands and CYP1A1 inducers was their potency (Table 9). Since monoortho coplanar PCBs competitively bind to the Ah receptor, these compounds should also elicit the biochemical and toxic responses comparable to other Ah receptor agonists. The results in Table 8 summarize the biochemical and toxic responses which have been observed for the monoortho coplanar PCBs and these include induction of CYP1A1 and CYP1A2 gene expression, induction of epoxide hydrolase, inhibition of body weight gain, immunosuppressive effects, thymic atrophy, hepatotoxicity, tumor promoter activity, antiestrogenicity, and reproductive and developmental toxicity. All of these responses were observed for the coplanar PCBs, TCDD and related toxic halogenated aromatics and appear to be mediated through the Ah receptor. Moreover, studies with genetically inbred C57BL/6 and DBA/2 mice also support a role for the Ah receptor in the induction and immunosuppressive responses elicited by monoortho coplanar PCBs 4l°433 494 49S. These data suggest that these same responses which are also caused by commercial PCB mixtures (Tables 4 through 6) are due, in part, to the individual coplanar and monoortho coplanar PCBs present in these mixtures. Moreover, since some of the monortho coplanar PCBs are present in relatively high concentrations in commercial mixtures and environmental extracts, this class of PCBs may contribute significantly to the TCDD-like 28 activity of PCB mixtures. (iii) Other structural classes of PCBs. The activity of other structural classes of PCBs as Ah receptor agonists were also investigated by determining their activity as inducers of CYP1A1 and CYP1A2 4ff7^09-4U. The 13 possible diortho substituted coplanar PCBs were synthesized and evaluated as inducers in rodents and most of these compounds, including 2,3,4,4',5,6-hexaCB, 2,2',3,3',4,4'-hexaCB, 2,2',3',4,4',6-hexaCB, 2,3,3',4,4',6-hexaCB, 2,2'.3,3',4,4',5-heptaCB, 2,2',3,4,4',5,5'-heptaCB, 2,3,3',4,4',5,6-heptaCB, 2,3,3',4,4',5',6- heptaCB and 2,3,3',4,4',5,5',6-octaCB, induced AHH activity and/or the CYP1A1 isozyme 407-W9.4ii -j^g activities Of the diortho coplanar PCBs as CYP1A1 inducers have been reported in other studies u 188 52° and the results confirm that with the possible exception of 2,2',4,4',5,5'-hexaCB, the diortho coplanar PCBs exhibit weak Ah receptor agonist activity. Moreover, limited studies have shown that some of these congeners cause porphyria in rats (2,2',3,4,4',5'-hexaCB and 2,2',3,3',4,4'-hexaCB) "° and inhibit the splenic PFC response to SRBCs in C57BL/6 mice (2,3',4,4',5',6-hexaCB) uo. It has also been reported that coplanar and monoortho coplanar PCB congeners in which one para substituent has been removed (e.g. 3,3',4,5,5'-pentaCB, 2,3,3',4,5'-pentaCB and 2,3,3',4,5,5'- hexaCB) also exhibited some weak Ah receptor agonist activity I4°- *°3. Since the potencies of these compounds and the diortho coplanar PCBs are weak compared to the coplanar and monoortho coplanar PCBs, it is unlikely that they play a major role in the TCDD-like" activity of the commercial PCBs and environmental PCB residues 45°. (b) "PB-Like" PCBs and Their Role in PCB-Induced ToxicUy The "mixed-type" monooxygenase induction activity exhibited by commercial PCBs indicates that some of the observed responses must be due to congeners which exhibit "PB- 29 like" activity. The monoortho and diortho coplanar PCBs constitute two structural classes of PCBs which exhibit "PB-like" induction activity and 2,2',4.4',5,5'-hexaCB is a congener which has been utilized as a prototypical "PB-type" inducer 189•'"•4"•419. 2,2',4,4',5,5'- HexaCB and the structurally-related 2,2',4,4'-tetraCB are both substituted in at least two ortho and two para positions and induce CYP2B1 and CYP2B2 in rat liver4". In addition, many of the PB-type PCBs induce CYP3A isozymes which are prototypically induced by glucocorticoids such as dexamethasone 474. Many of the most active "PB-type" inducers contain at least two ortho and two para chlorine substituents 145; however, no comprehensive structure-activity rules have been developed for "PB-type" inducers since congeners with a variety of chlorine substitution patterns in the ortho-, para- and mera-position exhibit "PB- type" induction activities. Rodman and coworkers434 have also reported that several tri- and tetraortho-substituted PCB congeners which induced benzphetamine jV-demethylase activity and P450 levels in cultured chick embryo hepatocytes also induce EROD activity and cause the accumulation of uroporphyrin. The latter two effects occur at relatively high dose levels and may represent examples of Ah receptor-independent responses which are also elicited by Ah receptor agonists at much lower concentrations43S. The only unambiguous structure- induction relationship for PCBs as "PB-type" inducers is that the coplanar 3,3',4,4'-tetraCB, 3,3',4,4',5-pentaCB and 3,3',4,4',5,5'-hexaCB congeners do not induce the "PB-like" drug- metabolizing enzyme activity. Inspection of the data for the structurally diverse PCBs which resemble PB as inducers indicates that with the exception of hepatomegaly and some hepatotoxic effects 72 197,299^ tnese compounds do not cause most of the putative Ah receptor-mediated responses observed in experimental animals after exposure to the coplanar and monoortho coplanar 30 PCBs and the commercial mixtures although the reproductive toxicity of other congeners has been reported 445. One major exception to this observation is associated with PCB-induced tumor promoter activity. Several compounds including 2,2',5,5 '-tetraCB466,2,2',4,5 '-tetraCB and 2,2',4,4',5,5'-hexaCB which induce PB-like activity also promote the formation of enzyme-altered preneoplastic focal lesions in rodents 116' "7 316. These results suggest that "PB-type" PCBs and possibly other structural classes of PCBs may be important contributors to the activity of the commercial mixtures as tumor promoters and this is an area of PCB structure-function relationships which requires further investigation. (c) PCBs Which Induce Neurotoxicity Several studies have reported the 3,3',4,4'-tetraCB causes neurotoxic and neurobehavioral changes in rodents and these include a permanent motor disturbance or "spinning syndrome" and other changes in neuromuscular activity 129 M7 M8 and alteration in cholinergic muscarinic receptors 161- '". Exposure of the nonhuman primate, Macaca nemestrina, to Aroclor 1016 resulted in decreased dopamine levels in specific regions of the brain including the caudate, hypothalamus, substantia nigra and putamen 483. Gas chromatographic analysis of brain samples identified only three congeners, namely, 2,4,4'- triCB (Figure 5), 2,2',4,4'-tetraCB and 2,2',5,5'-tetraCB. Subsequent studies have demonstrated that these compounds and other o/t/io-substituted PCBs (but not the coplanar PCB congeners) caused a concentration-dependent decrease in dopamine levels in PC-12 pheochromocytoma cells4M 4*7. Thus, these results define a new structural class of PCBs other than Ah receptor agonists which elicit neurotoxic responses. It has been hypothesized that these compounds may play a role in the neurobehavioral deficits in infants associated with in utero exposure to PCBs; however, this in an area of research which requires further 31 study to validate or invalidate this hypothesis. (d) Toxic and Biochemical Responses Associated with PCB Metabolites The metabolism of PCBs has been extensively reviewed ***•478 50° 5" and a summary of the major metabolic pathways is shown in Figure 4. PCBs are metabolized either directly or via arene oxide intermediates into phenolic metabolites which can be further hydroxylated or conjugated to form catechols and phenolic conjugates, respectively. The highly unstable arene oxides also react to form dihydrodiols, glutathione conjugates and covalently-bound protein, RNA and DNA adducts. Since oxidative metabolism of xenobiotics is a major route for the detoxication and ultimate elimination of the more hydrophilic metabolites, initial studies on PCBs focused primarily on the toxicity and genotoxicity associated with the formation and subsequent reactions of arene oxide intermediates. Several reports have shown that in vivo and in vitro metabolic activation of PCBs resulted in the formation of protein, RNA and DNA adducts and increased DNA repair in mammalian cells J6S 478'479-49°. 49i, 5M. 5»6 However, the PCBs which are readily metabolized and form arene oxide intermediates are the lower chlorinated congeners or those compounds which contain two adjacent unsubstituted carbon atoms. With the exception of 3,3',4,4'-tetraCB, most of the toxic coplanar and monoortho coplanar PCB are not readily metabolized. Moreover, treatment of Wistar rats with Aroclor 1254, one of the more toxic commercial PCBs, did not result in formation of DNA adducts as determined by 32P-postlabeling 383. Thus, it is unlikely that metabolic activation plays a major role in PCB-induced toxicity and genotoxicity. PCBs undergo metabolism to form hydroxy metabolites or their conjugates which are readily conjugated and excreted by laboratory animals. The toxicities of several hydroxy- 32 PCB metabolites have been evaluated and compared to the effects of their parent hydrocarbons 293'297 514 5I5 588 597. 3,3',4,4'-Tetrachloro-5-biphenylol and 3,3',4',5-tetrachloro- 4-biphenylol, the two major rat urinary metabolites of 3,3',4,4'-tetraCB, were considerably less toxic than the parent hydrocarbon and did not induce Ah receptor-mediated responses 5%. Similar results were observed for the rat urinary metabolites of 3,3',4,4',5-pentaCB. In a parallel study, the chick embryotoxicity of the hydroxylated metabolites of 3,3',4,4'-tetraCB were at least two orders of magnitude less toxic than the parent hydrocarbon 293. Thus, it is unlikely that the Ah receptor-mediated biochemical and toxic responses caused by the commercial PCB mixtures (Tables 4 through 6) and individual congeners are caused by the hydroxylated metabolites. However, hydroxylated PCBs are not devoid of biological activity. For example, hydroxylated PCB congeners can act as uncouplers and inhibitors of mitochondrial oxidative phosphorylation '"•376-389> 39°; hydroxylated PCBs competitively bind to the estrogen receptor and increase mouse uterine wet weight in vivo 30i; hydroxylated PCBs inhibit various P450- dependent enzyme activities 476; and hydroxylated PCBs bind prealbumin, a major serum thyroxine binding protein428. It has also been reported that hydroxylated PCB metabolites are selectively retained in the serum of rats and this was due to high affinity binding to a thyroxine transport protein, transthyretin (TTR)96-100'292. For example, 3,3',4',5-tetrachloro- 4-biphenylol (Figure 5), a major metabolite of 3,3',4,4'-tetraCB, exhibited higher TTR binding affinity than thyroxine, the endogenous hormone. Preliminary results indicate that hydroxylated PCBs are present in serum of wildlife and human samples 292. It has been hypothesized that some PCB-induced toxic responses may be due to the interaction of hydroxylated PCBs with I IK and other endogenous receptors; however, this suggestion 33 requires further validation. The metabolism of PCBs also results in the formation of glutathione conjugates which are excreted in the bile and undergo microbial C-S lyase cleavage in the intestine. Methylation of the resulting thiols followed by reabsorption and S-oxidation yields methylsulfonyl PCB metabolites which have been identified in human and animal serum and several organs/tissues42'6M6-193'2a 2U-262'42a 421-424- <"•576-578. Using 4,4'-bis(methylsulfonyl)- 2,2',5,5'-tetrachlorobiphenyl (Figure 5) as a model it has been shown that this metabolite preferentially accumulates in the lung and kidney and binds with high affinity (K^ — 109 M) to a constitutive protein which resembles uteroglobin 95 338 "9. This compound also binds with high affinity to rabbit uteroglobin 181 and fatty acid binding proteins in chicken liver and intestinal mucosa 319. Methylsulfonyl PCB metabolites and related binding proteins have been identified in humans213 "8. Methylsulfonyl PCB metabolites also inhibit induced AHH activity in both in vivo and in vitro models 289'291 337. Thus, both hydroxylated and methylsulfonyl PCB metabolites are biologically active and bind to endogenous proteins; however, the toxicological significance of these interactions has not been delineated. (e) PCB Interactions Since PCBs in commercial products and environmental samples are complex mixtures of isomers and congeners, their toxic interactions may be important determinants in the resulting toxicity of the mixtures. Several studies have investigated the interactions between individual PCB congeners and mixtures with other Ah receptor agonists such as TCDD and these studies serve as models for assessing the environmental interactions of PCBs with other halogenated aromatic hydrocarbons (HAHs) such as PCDDs and PCDFs. Denomme and coworkers reported that Aroclor 1254 and several PCB congeners significantly increased 34 rat hepatic cytosolic Ah receptor levels in rats U6. For example, eight days after administration of Aroclor 1254 or 2,2',4,4',5,5'-hexaCB, there was approximately a 2- or 3- fold increase in cytosolic Ah receptor levels which remained elevated for the 14-day duration of this study. Comparable results were noted in C57BL/6 mice 31. It was suggested that the 2,2',4,4',5,5'-hexaCB-induced receptor levels may synergistically enhance the biochemical and toxic responses elicited by Ah receptor agonists such as TCDD or coplanar PCB congeners. Cotreatment of C57BL/6 or DBA/2 mice with different concentrations of TCDD and 2,2',4,4',5,5'-hexaCB (500 /zmol/kg) resulted in a marked enhancement of TCDD-induced hepatic microsomal AHH and EROD activity at low doses of TCDD (1 nmol/kg) but not at higher doses (100 and 500 nmol/kg) 5I. The synergistic induction response was also noted in DBA/2 mice for several doses of TCDD (10, 25, 80, 200, 500 and 5000 /zmol/kg); however, the increased monooxygenase activity was less than 100% at all doses. 2,2',4,4',5,5'-HexaCB did not enhance TCDD-induced thymic atrophy or body weight loss in mice and the only significant interactive effect was protection of DBA/2 mice from TCDD-induced body weight loss. The interaction of 2,2',4,4',5,5'-hexaCB with 3,3',4,4',5-pentaCB and 2,3,3',4,4',5-hexaCB was also investigated in the male Wistar rat322. The interactive effects between the PCB congeners on toxicity and EROD induction were minimal and similar results were reported for the interaction of 2,2',4,4',5,5'-hexaCB and 1,2,3,7,8-pentachlorodibenzo-p-dioxin "". Non-additive (synergistic) interactions of 2,2',5,5'- and 3,3',4,4'-tetraCB as promoters of hepatic preneoplastic lesions in rats have also been reported 4*6; however, the nature and significance of these interactions requires further confirmation by dose-response studies. It has also been reported that individual PCB congeners and commercial mixtures 35 exhibit Ah receptor antagonist activity 50 71 139- ua 208. Davis and Safe 139 showed that Aroclors 1260, 1254, 1248, 1242, 1016 and 1232 caused a dose-response inhibition of the splenic PFC response to SRBCs in C57BL/6 mice and the ED50 values for this immunosuppressive effect varied from 104 to 464 mg/kg. These data indicate that the commercial PCBs were relatively weak Ah receptor agonists for this response since the corresponding ED50 value for TCDD was 0.77 jig/kg. The interaction of the commercial PCBs with TCDD (1.2 Mg/kg) showed that Aroclors 1232, 1252, 1248, 1254 and 1260 significantly inhibited TCDD-induced immunotoxicity in C57BL/6 mice (Table 10). Table 11 summarizes the results obtained for the interactions of Aroclor 1254 and TCDD for several effects in C57BL/6 mice; it is evident that the % maximum antagonism is response- dependent and ratios of Aroclor 1254/TCDD, <20,000/1 and > 1670/1, are required to observe partial antagonism. Analytical studies of extracts from human tissues and environmental extracts have shown that the ratios of PCBs/PCDDs plus PCDFs is in the range which is required for PCB-mediated antagonism of TCDD-induced responses in laboratory animal studies; however, the significance of PCB/PCDD plus PCDF interactions in wildlife species and humans is unknown. Individual PCB congeners which exhibit partial Ah receptor antagonist activity have also been identified "• 140-36S. 2,2',4,4',5,5'-HexaCB at high doses (400 to 1000 /*mol/kg) partially antagonized TCDD-induced EROD activity, immunotoxicity and teratogenicity in C57BL/6 mice. For example, the results summarized in Table 12 71 demonstrate that 2,2',4,4',5,5'-hexaCB completely protected C57BL/6 mice from TCDD-induced inhibition of the PFC response to SRBCs and comparable protection was observed for TCDD-induced teratogenicity. The mechanism of these interactions was unclear since no binding was 36 125 observed between [ I2]4,4'-diiodo-2,2',5,5'-tetrachlorobiphenyl (an analog of 2,2',4,4',5.5'- hexaCB) and the cytosolic Ah receptor or any other cytosolic protein. Davis uo also identified other PCB congeners which inhibited TCDD-induced immunotoxicity; however, these congeners were considerably less active than Aroclor 1254 or 2,2',4,4',5,5'-hexaCB as partial antagonists. The non-additive (antagonistic) PCB/TCDD interactions in mice suggests that in complex mixtures of PCBs, PCDDs and PCDFs the former compounds may suppress the activity of other Ah receptor agonists in the mixture. The non-additive interactions of other complex mixtures of PCBs have not been extensively investigated. Reconstituted PCB mixtures of individual PCB congeners which have been identified in human milk samples have been investigated and these mixtures exhibit many of the same partial Ah receptor agonist and antagonist activities reported for the PCB mixtures 1Mi 2 The toxicity of Clophen A50, Aroclor 1254 and fractions of the commercial PCBs containing nonortho-, monoortho-, di-tetraortho-substituted PCBs and tricyclic impurities (e.g. PCDFs) were investigated in mink 28°. The commercial products, monoortho and nonortho PCB fractions, caused reproductive impairment; the results showed that both fractions exhibited comparable toxic potencies and indicated that the monoortho PCBs which are less toxic than the coplanar PCBs are important contributors to the toxicity of the mixture due to their relatively high concentrations. The authors also report that in cotreatment studies the diortho- to tetraortho-substituted PCB fraction enhanced the reproductive toxicity of both the nonortho- and monoortho-substituted PCB fractions. The effects of commercial PCBs and the different fractions on several other responses in mink 37 were also investigated and these included effects on blood parameters l", steroid hormone excretion M2, P450 induction '", vitamin A levels 2l°, liver histology 67, and morphology of the reproductive organs37. The relative potencies of the individual fractions and the commercial mixtures were highly variable and response-specific. For example, elevation of serum enzymes indicative of liver damage appeared to be associated with the non-ortho PCB fraction but this activity was enhanced by cotreatment with the di- to tetraortho PCB fraction. Decreased vitamin A levels were primarily due to the non-ortho and monoortho PCB fractions 21°. These data are at variance with the reported antagonism of TCDD- induced responses by Aroclors and 2,2',4,4',5,5'-hexaCB in mice; therefore the interactive effects of nonortho- and monoortho-substituted with di- to tetraortho-substituted PCB fractions should be further investigated in other laboratory animals to determine the species- and response-specificity of these interactions. VI. DEVELOPMENT AND VALIDATION OF THE TOXIC EQUIVALENCY FACTOR (TEF) APPROACH FOR THE RISK ASSESSMENT OF PCBs (a) Background - Derivation of TEFs for PCDDs and PCDFs PCBs, PCDDs and PCDFs are routinely detected as complex mixtures of isomers and congeners in almost every component of the global ecosystem 148 26° 4Sl 4" 537. These compounds are not intentionally produced but are formed as by-products of numerous industrial activities including the synthesis of diverse chlorinated aromatics, particularly the chlorinated phenols and their derived products, production and smelting of metallic ores, pulp and paper production, and in the combustion of municipal and industrial wastes 451. Despite the complex composition of many PCDD/PCDF-containing wastes, the congeners 38 which persist in the environment and bioconcentrate in the food chain are the lateral 2,3.7,8- substituted congeners namely 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or 2,3,7,8- tetraCDD), 1,2,3,7,8-pentaCDD, 1,2,3,6,7,8-hexaCDD, 1,2,3,7,8,9-hexaCDD, 1.2,3,4,7,8- hexaCDD. 1,2,3,4,6,7,8-heptaCDD, octaCDD, 2,3,7,8-tetrachlorodibenzofuran (tetraCDF), 1,2,3,7,8-pentaCDF, 2,3,4,7,8-pentaCDF, 1,2,3,4,7,8-hexaCDF, 1,2,3,6,7,8-hexaCDF, 1,2,3,7,8,9- hexaCDF,2,3,4,6,7,8-hexaCDF,l,2,3,4,6,7,8-heptaCDF,l,2,3,4J,8,9-heptaCDFandoctaCDF. The relative and absolute concentrations of these congeners in both pollution sources and environmental matrices are highly variable. For example, octaCDD is the dominant congener which persists in all human serum and adipose tissue samples whereas this congener is a minor component in PCDD/PCDF extracts from fish 4SI. Risk assessment of PCDDs/PCDFs initially focused on one congener, namely TCDD which is the most toxic member of this class of compounds. However, with the improvement of analytical methodologies it was demonstrated that in many industrial and environmental samples that TCDD was present in relatively low concentrations. Moreover, based on structure-toxicity relationships 193 420'421> "*• 45° 376-578 which were developed for the PCDDs and PCDFs, it was recognized that in addition to TCDD many of the 2,3,7,8-substituted PCDDs and PCDFs were also highly toxic and were major contributors to the overall toxicity of these mixtures. Based on structure-activity, genetic and molecular biology studies, it is generally accepted that most of the toxic responses elicited by the PCDDs, PCDFs, coplanar and monoortho coplanar PCBs are mediated through the Ah receptor. One of the hallmarks of receptor-mediated responses is the stereoselective interaction between the receptor and diverse ligands and the rank order correlation between structure-binding and structure- 39 toxicity relationships for most of these ligands. Thus, based on these mechanistic considerations, a TEF approach has been adopted by most regulatory agencies for the risk assessment of PCDDs and PCDFs 2-5'52-62-3I5-3M-450. All the relevant individual congeners have been assigned a TEF value which is the fractional toxicity of the congener relative to a standard toxin, namely TCDD. Thus, if the ED50 values for the immunosuppressive activity of TCDD and 1,2,3,7,8-pentaCDD were 1.0 and 2.0 fig/kg, respectively, then the TEF for the latter compound would be the ratio ED50 (TCDD)/ ED^ (1,2,3,7,8-pentaCDD) or 0.5. The relative potencies or TEF values have been determined for several different Ah receptor-mediated responses and, for every congener, the TEF values are highly response- and species-dependent 45°. For example, the TEFs for 2,3,7,8-TCDF obtained from in vivo and in vitro studies varied from 0.17 to 0.016 and 0.43 to 0.006, respectively. Regulatory agencies have chosen single TEF values for all the PCDD/PCDF congeners (Table 13) and the selection criteria include the relative importance of data obtained for specific responses (e.g. carcinogenicity, reproductive and developmental toxicity) and for chronic studies since these effects and duration of exposure are important for protecting human and environmental health. It should be noted that proposed TEFs are interim values which should be reviewed and revised as new data becomes available. There are reports which indicate that the single value TEF approach for PCDDs and PCDFs can be successfully used to predict the toxicity of complex mixtures of PCDFs and PCDDs/PCDFs in laboratory animals 151-450. Thus, despite the range of experimental TEFs, the TEF values used for risk management can be utilized to predict the Ah receptor- mediated toxicity of PCDF/PCDD mixtures and suggesting that any non-additive interactive effects are minimal. The major application of the TEF approach has been the conversion 40 of quantitative analytical data for PCDD/PCDF mixtures into TCDD or toxic equivalence (TEQ) where [PCDF], and [PCDD], represent the concentrations of the individual congeners, TEF, is their corresponding TEF and n is the number of congeners. Thus, the . TEQ = £ ( [ PCDF, * 7ZF, ]„ ) + £ ( [ PCDDt , x TEFt ]„ ) concentrations of a complex mixture of PCDDs and PCDFs in a sample can be reduced to a single TEQ value which represents the calculated concentration of TCDD equivalence in that sample. The TEQs for PCDDs/ PCDFs have been determined for several types of mixtures including extracts from industrial and combustion processes, fish and wildlife samples, various food products, and human serum and adipose tissue. For example, based on the analysis of food products and their consumption, the daily human dietary intake of TEQs in Germany was estimated as 41.7 (milk and milk products), 39.0 (meat, meat products and eggs), 33.9 (fish and fish products), 6.3 (vegetables and vegetable oils) and 9.4 pg/person (miscellaneous food products) ". The estimated total daily intake was 130 pg/person and only 15% of this total was due to TCDD alone. The daily intake of PCDDs/PCDFs was estimated as 2 pg/kg/day (TEQs). This value is within the 1 to 10 pg/kg/day range of acceptable daily intakes recommended by most regulatory agencies with the exception of the U.S. Environmental Protection Agency which has utilized a value of 0.006 pg/kg/day. The significant differences between the USEPA and other regulatory agencies are based on their calculation methods and assumptions 413-492. For example, the USEPA assumes that TCDD is a complete carcinogen 296 and their value of 0.006 is derived from the linearized dose model which assumes no threshold for the response and protects the exposed population from one additional cancer per 106 individuals. In contrast, most 41 other regulatory agencies use the same carcinogenicity data 296 but utilize a safety factor approach in which it is assumed that TCDD is a promoter and there is a threshold for this response. The disparity between the USEPA value of 0.006 pg/kg data and the current intake of 2 pg/kg/day of TEQs is of concern and is currently being reevaluated by the agency 73-l67. (b) Development of TEFs for Coplanar and Monoortho Coplanar PCBs The results summarized in Tables 7 through 9 demonstrate that the coplanar and monoortho coplanar PCBs are Ah receptor agonists. Thus, any calculation of TEQs for industrial, environmental, food or human samples is incomplete unless the estimated "TCDD-like" activities of other Ah receptor agonists such as PCBs are included. Safe 45° has previously reviewed the QSAR studies for the coplanar PCBs and an updated summary of these data are given in Table 14. In some of these studies, the comparison of the toxic and biochemical potencies of the coplanar PCBs with TCDD are not given. In other reports 85 only the TEFs or a comparison of the maximal effects doses 435 were provided and not the EDso/ECso values. The results show that with few exceptions 3,3',4,4',5-pentaCB is the most active PCB congener in every assay system; however, the response-specific TEF values are highly variable (Table 15). In short term (14 day studies), the TEFs for body weight loss, thymic atrophy, and AHH and EROD induction in the rat varied from 0.093 to 0.015. These data were determined from the ratios of the ED50 (TCDD)/ED50 (3,3',4,4',5- pentaCB) for the different responses. Van Birgelen and coworkers561 calculated TEF values by comparing the ratios of the no observed effect levels (NOELs) and lowest observed effects levels (LOELs) for TCDD and 3,3',4,4',5-pentaCB based on their modulation of 42 thyroid hormone levels, liver and thymus weights, body weight gain and induction of EROD activity. In this study, the compounds were administered in the diet for 3 months and preliminary results indicate that the TEFs varied from 0.6 to 0.06 and were higher than observed in the 14 day study. The inhibition of the splenic PFC response to SRBCs M7 and trinitrophenyl-lipopolysaccharide (TNP-LPS) 216 antigens by 3,3',4,4',5-pentaCB has been determined in C57BL/6 and DBA/2 mice and the TEF values for immunotoxicity varied between 0.08 and 0.77. In contrast, the TEF for 3,3',4,4',5-pentaCB-induced teratogenicity was approximately 0.07 to 0.04. Several studies have reported the induction effects of 85 589 3,3',4,4',5-pentaCB in chick embryos and chick embryo hepatocytes " ; the TEFs varied from 0.1 to 0.017 and this range was lower than the corresponding induction-derived TEFs (0.32 to 0.40) in rat hepatoma H4II-E cells. Flodstrom and coworkers m estimated that the TEF for tumor promoter activity using the rat liver model was 0.1. With the exception of the low TEF observed for early life stage mortality in rainbow trout (Le. 0.003), the TEFs for 3,3',4,4',5-pentaCB varied between 0.77 to 0.015 and the mean value for the TEFs summarized in Table 15 was 0.19 ± 0.22. However, based on the tumor promotion- and teratogenicity-derived TEFs, the value of 0.1 proposed by Safe 45° represents a reasonable TEF for 3,3',4,4',5-pentaCB. The biochemical and toxic potencies and the derived TEF values for 3,3',4,4'-tetraCB and 3,3',4,4',5,5'-hexaCB are summarized in Tables 14 and 15 and the range of experimentally-derived TEF values varied from 7.0 x 10"* to 0.13 and 5.9 x 10"* to 1.1, respectively. These variations were not totally unexpected for 3,3',4,4'-tetraCB since this congener is rapidly metabolized in rats and many of the lowest TEFs were observed in this species 321. In contrast, the TEF values for inhibition of the splenic PFC response to SRBCs 43 in C57BL/6 mice M7 were considerably higher (0.13 to 0.03) than TEFs derived from 14-day studies in the rat. Sargent and coworkers 467 also compared the tumor promoting potencies of 3,3',4,4'-tetraCB and TCDD in the rat liver model and the TEF for this response was 0.029. The mean of the 14 TEFs in Table 15 and the 0.29 value for tumor promotion is 0.018 ± 0.034. Several of the 3,3',4,4'-tetraCB-induced responses summarized in Table 14 were not used in these calculations due to the lack of data for TCDD. However, TEFs can be estimated for both 3,3',4,4'-tetraCB and 3,3',4,4',5,5'-hexaCB by calculating the ED50 (3,3',4,4',5-pentaCB)/ED5o(3,3',4,4'-tetraCB) ratios and multiplying this ratio by 0.1 (ie. the TEF for 3,3',4,4',5-pentaCB). This calculation gives the following estimated TEFs for 3,3',4,4'-tetraCB: 0.036 (LD50 - chick embryos); 0.0055 (EROD induction - chick embryos); 0.009 (inhibition of lymphoid development - chick embryos); 0.008 (inhibition of bursal lymphoid development - chick embryos). The mean of these four TEFs was 0.014; the combined mean for all the responses was 0.017 ± 0.030. Thus, based on the experimental data, a reasonable TEF value for 3,3',4,4'-tetraCB would be 0.02 and this is higher than the 0.01 value proposed by Safe 45°. A similar approach can be taken for calculating the mean TEF for 3,3',4,4',5,5'- hexaCB based on the data summarized in Table 14. A TEF of 0.13 is a mean of 14 responses and this value decreases to 0.053 ± 0.089 if the unusually high immunotoxic TEF (1.1) is deleted from this calculation. In addition, estimation of TEFs for 3,3',4,4',5,5'- hexaCB relative to 3,3',4,4',5-pentaCB as noted above gave values of 0.0018 (LD50 - chick embryos), 0.0067 (EROD induction - chick embryos), 0.0012 (inhibition of lymphoid development - chick embryos), 0.0013 (inhibition of bursal lymphoid development - chick embryos). The mean TEF for these responses was 0.0012. Thus, the TEFs for 3,3',4,4',5,5'- 44 hexaCB range from 0.00059 to 1.1; Safe 45° assigned a TEF of 0.05 which is lower than the average of the responses noted in Tables 14 and 15 but higher than the 0.0012 values obtained for the effects in chick embryos. The assignment of a final TEF value for 3,3',4,4',5,5'-hexaCB should await the results of further studies; howeverrthe proposed TEF 450 of 0.05 may be useful on an interim basis. The relative potencies and TEFs for several monoortho coplanar PCBs are summarized in Table 16. For risk management of this structural class of PCBs, TEFs should be determined for the major congeners present in the commercial mixtures and environmental samples, namely, 2,3,3',4,4'-pentaCB, 2,3',4,4',5-pentaCB and 2,3,3',4,4',5- hexaCB. Safe 45° proposed a TEF of 0.001 for all the monoortho coplanar PCBs; however, this value may be too high based on the results given in Table 16. Mean TEFs of 0.00098 ± 0.002, 0.000088 ± 0.000096 and 0.00040 ± 0.00043 were observed for 2,3,3',4,4'-pentaCB (10 responses), 2,3',4,4',5-pentaCB (11 responses) and 2,3,3',4,4',5,-hexaCB (14 responses), respectively. Based on these data, the following interim TEFs are proposed for the monoortho coplanar PCBs: 0.001, 0.0001 and 0.0004 for the 2,3,3',4,4'-pentaCB, 2,3',4,4',5- pentaCB and 2,3,3',4,4',5-hexaCB congeners, respectively (Table 17). In addition, the mean TEFs for 2,3,3',4,4',5'-hexaCB, 2',3,4,4',5-pentaCB and 2,3,4,4',5-pentaCB were 0.00029, 0.00005 and 0.00019, respectively, and the suggested TEFs for these compounds are 0.0003, 0.00005 and 0.0002, respectively. Recent studies have reported the relative induction potencies of the coplanar PCBs, 2,3,3',4,4'-pentaCB, 2,3,3',4,4',5-hexaCB and 2,3,3',4,4',5'-hexaCB, administered 5 days per week by gavage to female B6C3F1 mice for 4 weeks. The relative induction potencies of these congeners were estimated by comparing their induced EROD (P4501A1) and 45 acetanilide-4-hydroxylase (P4501A2) activities to that observed for TCDD. The estimated TEFs were < 0.1 (3,3',4,4',5-pentaCB), < 0.00001 (3,3',4,4'-tetraCB), < 0.05 (3,3',4,4',5.5'- hexaCB), < 0.00005 (2,3,3',4,4'-pentaCB), < 0.001 (2,3,3',4,4',5'-hexaCB), and < 0.0005 (2,3,3'A4',5-hexaCB). Some of these estimated TEFs are higher and others lower than the values proposed in Table 17. However, the induction-derived TEFs in the female B6C3F1 mice were consistent with the induction-derived TEFs obtained from single dose experiments in male Wistar rats 32t. (e) Application of TEFs Derived for PCBs TEFs for PCDDs/PCDFs have been extensively used to determine TEQs in industrial, commercial and environmental mixtures of these compounds. Tanabe and coworkers 26M7l> 529'53S were the first to develop analytical techniques to quantitate coplanar PCBs in various mixtures and they initially determined PCB-derived TEQs utilizing TEFs derived from the relative potencies of PCB congener-induced AHH and EROD activities in rat hepatoma H4II-E cells 469. Their results showed that the TEQs for PCBs in most extracts from environmental samples or human tissues exceeded the TEQs calculated for the PCDDs/PCDFs in these same extracts. The results in Table 18 summarize the calculation of TEQ values in human adipose tissue samples based on the TEF values and the concentrations of individual PCDDs, PCDFs and PCBs present in this sample. The data indicate that the TEQs for the PCB fraction are higher than those for the combined PCDDs/PCDFs and comparable results have been observed in other studies 30 148 M9 537. (d) Validation and Limitations of the TEF Approach 46 The potential interactions of different structural classes of PCB congeners may have important implications for the risk assessment of PCBs, PCDDs and PCDFs. Previous studies have demonstrated that Aroclor 1254 and other PCB congeners inhibit TCDD- induced enzyme induction, teratogenicity and immunotoxicity in C57BL/6 mice 50 7I 139 14° 208 and it is conceivable that for PCB mixtures the interactions would also decrease coplanar PCB-induced toxicity. These potential inhibitory interactions between different structural classes of PCBs would result in overestimation of the toxicity of PCB mixtures using the TEF approach. Davis and Safe 139 reported the effects of various Aroclors on the inhibition of the splenic PFC response to SRBC in C57BL/6 mice. This effect is one of the most sensitive indicators of exposure to Ah receptor agonists. The concentrations of coplanar and monoortho coplanar PCBs in these mixtures have been reported and are summarized in Table 19. Unfortunately, the immunotoxicity-derived TEFs are available only for 3,3',4,4',5- pentaCB (0.45), 3,3',4,4'-tetraCB (0.13), 3,3',4,4',5,5'-hexaCB (1.1) and 2,3,3',4,4',5-hexaCB (0.0011) (see Tables 15 and 16); however, these values can be used to estimate the TEQs for these four congeners in Aroclors 1016, 1242, 1254 and 1260 (note: the analysis of the coplanar and monoortho coplanar PCBs has been determined 27° 48°. The TEQs for these Aroclors can be calculated from the immunotoxicity-derived TEFs and the concentrations of the individual PCBs in these mixtures (Le. TEQ = £ [PCBf x TEFJJ. The results in Table 20 summarize the calculated TEQs and ED50 values for the immunotoxicity of the commercial PCBs using TEQs only derived from only four of the coplanar and monoortho coplanar PCBs. The calculated ED50s are maximum values since the contributions from Ah receptor agonists other than the compounds noted above have not been included in the calculation. In all cases, the calculated ED50 values are significantly lower than the observed 47 ED50 values and the ratios of ED50 (observed)/ED50 (calculated) were 7.1, 22.5, 364 and oc for Aroclors 1260, 1254, 1242 and 1016. These values represent the fold-overestimation of PCB-induced immunotoxicity in C57BL/6 mice if the TEF approach is used. The data suggest that there are non-additive (antagonistic) interactions between the PCB congeners in these mixtures and this is consistent with the results of comparable antagonistic interactions between PCBs and TCDD I39 14°. Recent studies in this laboratory have investigated the dose-response induction of hepatic microsomal AHH and EROD activities by Aroclor 1232, 1242, 1248, 1254 and 1260 in male Wistar rats and the ED50 values were 137, 84, 51, 92 and 343 mg/kg (for AHH induction) and 678, 346, 251, 137, 442 mg/kg (for EROD induction), respectively m. Since the induction-derived TEF values for the coplanar and monoortho coplanar PCB congeners in rats have been determined (Tables 15 and 16) and their concentrations in Aroclors 1242, 1254, 1260 are also known (Table 19) then the TEQ values can be readily calculated (Table 21). The results show that with one exception there was less than a 2-fold difference between the observed versus calculated ED50 values; these data suggest that for AHH and EROD induction in the rat by the commercial PCBs, the interactive effects were minimal. Using a similar approach, it has been shown that for the induction of AHH and EROD activity by PCB mixtures in rat hepatoma H4II-E there were also minimal interactive effects "k 47°. It has previously been reported that there was a linear correlation between the - logECjo (in vitro induction) versus the -logEDso (in vivo responses) in rat hepatoma cells and rats, respectively 450-4i6; this would indicate that there are minimal non-additive interactions of PCBs for Ah receptor-mediated responses in rats such as thymic atrophy and body weight loss. Thus, the TEF approach is useful for estimating "TCDD-like" activity in rats and this 48 contrasts with the results obtained for immunotoxicity in mice in which the TEF approach significantly overestimate the immunotoxicity of PCB mixtures. The value of TEFs for risk management is dependent on minimal non-additive interactions among the PCBs, PCDDs and PCDFs. The results obtained in mice and rats for PCB mixtures illustrate that there are significant species and possibly response-specific differences in the non-additive antagonist interactions between PCBs and other Ah receptor agonists. Analysis of the data in rats supports the TEF approach for several responses (AHH and EROD induction, body weight loss and thymic atrophy); however, it is possible that there may be response-specific differences within the same animal species. Geisy, Tillitt and coworkers have utilized both in vitro and in vivo studies to investigate the role of TCDD-like" PCBs, PCDDs and PCDFs as possible etiologic agents in wildlife toxicity 545i546'58°l381 Tillitt and coworkers M5 extracted double-breasted cormorant eggs and determined their TEQ values for PCBs in these extracts using the rat hepatoma H4II-E cells as a bioassay. This assay provides TEQ values for mixtures and the results showed that there were minimal (non-additive) interactive effects as noted above 47°. In this study, their was a linear correlation between the PCB-TEQs in specific colonies and their reproductive success. These results suggest that this response may be Ah receptor mediated and that the 'TCDD-like" PCB congeners may be responsible for the observed reproductive toxicity. However, in a second study 5M the PCB-TEQs in extracts from Lake Michigan chinook salmon were determined by high resolution chemical analysis and there was not a correlation between the calculated PCB-TEQs and the mortality of eggs and fry from the different clutches. Most of the calculated TEQs were significantly higher than the observed total rearing mortality and this may be analogous to the immunotoxicity in mice in which 49 the calculated TEQs overestimate toxicity due to non-additive (antagonistic) interactions. It is also possible that the rearing mortality response is not Ah receptor-mediated and is due to other classes of toxic chemicals. Thus, the TEF approach can be used to calculate the TEQs of PCBs, PCDDs and PCDFs in extracts of environmental samples and in commercial mixtures. However, the results of laboratory animal and wildlife studies suggests that the predictive value of TEQs for PCBs, PCDDs and PCDFs may be both species- and response-dependent since both additive and non-additive (antagonistic) interactions have been observed. Therefore these data would suggest that TEFs for PCBs and other halogenated aromatics such as PCDDs and PCDFs should be used in risk management of these contaminants with considerable care. (e) Application of TEFs for Carcinogenic Potencies The development of regulations for PCBs and many other environmental toxins often utilizes data from long term rodent carcinogenesis bioassays. Many of the current regulations for PCBs are derived from the carcinogenicity of Aroclor 1260 392 in which it is assumed to be a complete carcinogen. However, since most studies indicate that the higher chlorinated PCBs are non-genotoxic 44'1493 and do not form persistent DNA adducts in vivo m, it is more likely that these mixtures act as cancer promoters as summarized in Table 5. The relative potencies of PCB mixtures as carcinogens or promoters have not been extensively investigated; however, the results suggest that the most active PCBs are the higher chlorinated mixtures such as Aroclor 1260 or Clophen A60 471. However, based on the concentrations of the coplanar and monoortho coplanar PCBs in the commercial 50 Aroclors and Clophens, the TEQs for Aroclor 1260 and Clophen A60 are lower than observed for low chlorinated mixtures such as Aroclors 1242, 1248 and 1254 ro • 5 Sprague Dawley rats and the results in Table 22 compare the .effects of dietary concentrations of TCDD and Aroclor 1260 on the development of hepatocellular carcinomas. The data illustrate a lack of correspondence between the calculated TEQ values and cancer potency for Aroclor 1260 and TCDD. The low TEQ value for Aroclor 1260 suggests that only a fraction of the carcinogenicity of this mixture is due to the "TCDD- like" congeners and that other structural classes of PCBs are major contributors to this response. As noted in section V(b), PB-type PCBs are also tumor promoters; these congeners predominate in higher chlorinated PCB mixtures and may play an important role in the carcinogenicity of Aroclor 1260. This is supported by the results of recent studies218 which showed that Aroclor 1260 was considerably more active than Aroclors 1232, 1242, 1248 and 1254 as inducers of CYP2Bl-dependent activity in rats and this also corresponded to the potencies of these mixtures as rodent carcinogens. The use of TEFs and TEQs for risk management is limited only to Ah receptor-mediated responses. Therefore, since the data summarized in Table 22 suggest that development of PCB-induced hepatocellular carcinomas in female Sprague-Dawley rats may primarily be an Ah receptor-independent response, the TEF/TEQ approach may not be appropriate for risk management based on this endpoint. The higher chlorinated PCBs such as Aroclor 1254 and Aroclor 1260 are poorly metabolized and it is likely that the carcinogenicity of these mixtures is associated with their activity as tumor promoters. Thus, cancer-based risk assessment of PCB mixtures requires additional data on the tumor-promoting potencies of the major congeners present 51 in these mixtures and environmental samples. VII. SUMMARY 1. Commercial PCBs and environmental extracts contain complex mixtures of isomers and congeners which can be identified and quantitated by chromatographic procedures. The environmental PCB residues do not resemble the commercial PCBs and congener-specific risk assessment of these mixtures is warranted. 2. The effects of occupational exposure to relatively high levels of PCBs resulted in a number of adverse responses which appear to be reversible. Epidemiological surveys of several occupationally-exposed groups did not reveal any increased incidence of specific cancers in all studies. Some reports showed increased incidence of cancer at different sites whereas in other studies no increases were observed. The major adverse human health effects associated with environmental exposure to PCBs may be neurodevelopmental deficits associated with in utero exposures. The role of PCBs or other as yet unidentified chemicals as etiologic agents for this response requires further investigation. 3. Commercial PCB mixtures elicit a broad spectrum of biochemical and toxic responses and most of these effects are similar to those caused by TCDD and other Ah receptor agonists. Two major structural classes of PCBs, namely the coplanar and monoortho coplanar PCBs exhibit Ah receptor agonist activity and appear to responsible for many of the PCB mixture-induced responses. 4. Other structural classes of PCB also elicit biochemical and toxic responses. PCBs which exhibit "PB-like" activity are also tumor promoters and these compounds 52 comprise a high percentage of higher chlorinated PCB mixtures. The results of most studies suggest that PCBs are not genotoxic but act as tumor promoters in several bioassays. Thus congener-specific regulation of PCBs based on their tumor- promoting activity must take into account the contributions of the "PB-like" congeners. This is an area of PCB risk assessment which requires further study. 5. Other structural classes of PCBs and PCB metabolites also exhibit diverse activities including neurotoxicity, estrogenicity, endogenous protein binding activities and inhibition of oxidative phosphorylation. The toxicologic role of these compounds in PCB-induced toxicity has not been determined. 6. Several studies have demonstrated that PCB mixtures and individual congeners inhibited TCDD-induced responses and these studies suggests that in some animal models and for some responses non-additive (antagonistic) interactions may be important. 7. TEFs for the coplanar and monoortho coplanar PCBs have been estimated: 3,3',4,4',5-pentaCB, 0.1; 3,3',4,4',5,5'-hexaCB, 0.05; 3,3',4,4'-tetraCB, 0.02; 2,3,3',4,4'-pentaCB, 0.001; 2,3',4,4',5-pentaCB, 0.0001; 2,3,3',4,4',5-hexaCB, 0.0003. These values can be used to calculate TEQs only for Ah receptor-mediated responses. 8. The calculated TEQs for various environmentally-derived extracts tended to be higher for the PCBs than the calculated TEQs for the PCDDs plus PCDFs. 9. The TEF approach for the risk assessment of PCBs must be used with considerable caution. The results of laboratory animal and wildlife studies suggests that the predictive value of TEQs for PCBs, PCDDs and PCDFs may be both species- and 53 response-dependent since both additive and non-additive (antagonistic) interactions have been observed with PCB mixtures. Moreover, analysis of the rodent carcinogenicity data for Aroclor 1260 using the TEF approach suggests that this response is primarily Ah receptor-independent. Thus, risk assessment of PCB mixtures which uses cancer as an endpoint requires more quantitative information on the PCBs congeners which contribute to the tumor promoter activity of these mixtures. ACKNOWLEDGEMENTS The financial support of the National Institutes of Health (P42-ES04917) and the Texas Agricultural Experiment Station is gratefully acknowledged. The author is a Burroughs Wellcome Toxicology Scholar. The invaluable assistance of Mrs. Kathy Mooney in the preparation of this manuscript is greatly appreciated. 54 REFERENCES 1. Addison, R.F.. M.E. Zinck. D.E. Willk, and D.C. Darrow. 1979. Induction of hepatic mixed function oxidascs in trout by polychlorinalcd biphenyls and butylatcd monochlorodiphcnyl ethers. Toxicol. Appl. Phannacol. 49:245-248. 2. AhJborg, U.G. 1989. Nordic risk assessment of PCDDs and PCDFs. Chemosphere 19:603-608. 3. Ahlborg, U.G., A. Brouwer, MA. Fingerhut, J.L. Jacobson, S.W. Jacobson, S.W. Kennedy, AA.F. Kettrup, J.H. Koeman, H. Poiger, C. Rappe, S.H. Safe, R.F. Seegal, J. Tuomisto, and M. Van den Berg. 1992. Impact of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls on human and environmental health with special emphasis on application of the toxic equivalence factor concept. Eur. J. Phannacol. 228:179-199. 4. Ahlborg, U.G., H. Hikansson, F. Wasrn, and A. Hanberg. 1988. Nordisk dioxinriskbedomning. Rapport fran en nordisk expertgrupp. Nordisk Ministerradet, Miljorapport. 5. Ahlborg, U.G., A. Hanberg, and K. Kenne. 1992. Risk Assessment of Polychlorinated Biphenyls (PCBs). Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. 6. Ahotupa, M. 1981. Enhancement of epoxide-metabolizing enzyme activities by pure PCB isomers. Biochem. Phannacol. 30:1866-1869. 7. Albrecht, W.N. 1987. Central nervous system toxicity of some common environmental residues in the mouse. /. Toxicol. Environ. Health 21:405-421. 8. Albro, P.W., J.T. Corbett, and J.L. Schroeder. 1981. Quantitative characterization of polychlorinated biphenyi mixtures (Aroclors 1248, 1254 and 1260) by gas chromatography using capillary columns./. Chromatogr. 205:103-111. 9. Albro, P.W. and C.E. Parker. 1979. Comparison of the composition of Aroclor 1242 and Aroclor 1016. /. Chromatogr. 169:161-166. 10. Alien, J.R. 1975. Response of the nonhuman primate to polychlorinated biphenyi exposure. Fed. Proc. 34:1675-1679. 11. Alien, J.R. and LJ. Abrahamson. 1973. Morphological and biochemical changes in the liver of rats fed polychlorinated biphenyls. Arch. Environ. Contam. Toxicol. 1:265-280. 12. Alien, J.R. and LJ. Abrahamson. 1979. Responses of rats exposed to polychlorinated biphenyls for 52 weeks. II. Compositional and enzymic changes in the liver. Arch. Environ. Contam. Toxicol. 8:191-200. 13. Alien, J.R., LA. Carsten, and LJ. Abrahamson. 1976. Responses of rats exposed to polychlorinated biphenyls for 52 weeks. I. Comparison of tissue levels of PCB and biological changes. Arch. Environ. Contam. Toxicol. 4:404-419. 14. Alien, J.R., LA. Carstens, and DA. Barsotti. 1974. Residual effects of short-term, low-level exposure of non-human primates to polychlorinated biphenyls. Toxicol. Appl. Phannacol. 30:440-451. 15. Alvares, A.P. 1977a. Stimulatory effects of polychlorinated biphenyls (PCB) on cytochromes P-450 and P-448 mediated microsomal oxidations. InMicrosomes and Drug Oxidations. V. Ullrich, A. Hildebrandt, I. Roots, R.W. Estabrook, and A.H. Conney, editors. Pergamon Press, Oxford. 476-483. 55 16. Alvares, A.P.. D.R. Bickers, and A. Kappas. 1973. Polychlorinated biphenyis: a new type of induccr of cytochrome P-448 in the liver. Proc. Natl. Acad. Sci. USA 70:1321-1325. 17. Alvares, A.P., A. Fischbein, K.E. Anderson, and A. Kappas. 1977b. Alterations in drug metabolism in workers exposed to polychlorinated biphenyis. Clin. Pharmacol. Tlierap. 22:140-146. 18. Alvares, A.P. and A. Kappas. 1977c. The inducing properties of polychlorinated biphenyis on hepatic monoxygenases. Clin. Pharmacol. Therap. 22:809-816. 19. Alvares, A.P. and A. Kappas. 1977d. Heterogeneity of cytochrome P-450s induced by polychlorinated biphenyis. /. Biol. Chem. 252:6373-6378. 20. AJvares, A.P. and A. Kappas. 1979. Lead and polychlorinated biphenyis: effects on heme and drug metabolism. Drug Metab. Rev. 10:91-106. 21. Alvares, A.P., T-H. Ueng, and J.L. Eiseman. 1982. Polychlorinated biphenyis (PCBs) inducible monooxygenases in rabbits and mice: species and organ specificities. Life Sciences 30:747-751. 22. Anderson, L.M., L.E. Beebe, S.D. Fox, H J. Issaq, and R.M. Kovatch. 1991. Promotion of mouse lung tumors by bioaccumulated polychlorinated aromatic hydrocarbons. Exp. Lung Res. 17:455-471. 23. Anderson, L.M., K, Van Havere, and J.M. Budinger. 1983. Effects of polychlorinated biphenyis on lung and liver tumors initiated in suckling mice by /V-nitrosodimethylamine. /. Natl. Cancer Inst. 71:157-163. 24. Anderson, R.S. 1978. Aryl hydrocarbon hydroxylase induction in an insect, Spodoptera eridania (Cramer), by polychlorinated biphenyis (PCBs). Comp. Biochem. Physiol. 60:51-55. 25. Andersson, L., E. Nikolaidis, B. Brunstrom, A. Bergman, and L. Dencker. 1991. Effects of polychlorinated biphenyis with Ah receptor affinity on lymphoid development in the thymus and the bursa of Fabricius of chick embryos in ovo and in mouse thymus anlagen in vitro. Toxicol. Appl. Pharmacol. 107:183-188. 26. Anonymous. 1966. Report of a new chemical hazard. New Scientist 32:621. 27. Aoki, Y., K. Satoh, K. Sato, and K.T. Suzuki. 1992. Induction of glutathione S-transferase P-form in primary cultured rat liver parenchyma! cells by co-planar polychlorinated biphenyi congeners. Biochem. J. 281:539-543. 28. Argus, M.F., G.M. Bryan, K.M. Pastor, and J.C. Arcos. 1975. Effect of polychJorinated biphenyis (Aroclor 1254) on inducible and repressible microsomal W-demethylases in the mouse and rat. Cancer Res. 35:1574-1579. 29. Arnold, D.L., J. Mes, F. Bryce, K. Karpinski, M.G. Bickis, Z.Z. Zawidzka, and R. Stapley. 1990. A pilot study on the effects of Aroclor 1254 ingestion by rhesus and cynomolgus monkeys as a model for human ingestion of PCBs. Fd. Chem. Toxic. 28:847-857. 30. Asplund, L., A-K. Grafstrom, P. Haglund, B. Jansson, U. Jarnberg, D. Mace, M. Strandell, and C. De Wit. 1990. Analysis of non-ortho polychlorinated biphenyis and polychlorinated naphthalenes in Swedish dioxin survey samples. Chemosphere 20:1481-1488. 31. Atlas, E. and C.S. Giam. 1981. Global transport of organic pollutants: ambient concentrations in the remote marine atmosphere. Science 211:163. 32. Aulerich, R J. and RJC Ringer. 1977. Current status of PCB toxicity to mink, and effect on their reproduction. Arch. Environ. Contam. Toxicol. 6:279-292. 56 33. Aulerich, R.J., R.K. Ringer, and J. Safronoff. 1986. Assessment of primary vs. secondary toxicity of Aroclor 1254 to mink. Arch. Environ. Contam. Toxicol. 15:393-399. 34. Ax. R.L. and L.G. Hansen. 1975. Effects of purified PCB analogs on chicken reproduction. Poult. Sci. 54:895-900. 35. Azais. V.. M. Arand, P. Rauch, H. Schramm, P. Bellenand, J-F. Narbonne. F. Oesch, G. Pascal, and L.W. Robertson. 1987. A time-course investigation of vitamin A levels and drug metabolizing enzyme activities in rats following a single treatment with prototypical polychlorinated biphenyls and DOT. Toxicology 44:341- 354. 36. Azais. V. and G. Pascal. 1986. Effects of congeneric polychlorinated biphenyls on liver and kidney retinoid levels. Chemosphere 15:1905-1908. 37. Backlin, B-M. and A. Bergman. 1992. Morphological aspects on the reproductive organs in female mink (Mustela visori) exposed to polychlorinated biphenyls and fractions thereof. Ambio 21:596-601. 38. Bacon. C.E., W.M. Jarman, and D.P. Costa. 1992. Organochlorine and polychlorinated biphenyl levels in pinniped milk from the Arctic, the Antarctic, California and Australia. Chemosphere 24:779-791. 39. Bahn. A.K., P. Grover, I. Rosenwaike, K. O'Leary, and J. Stellman. 1977. PCB and melanoma. N. Engl. J. Med. 296:108. 40. Bahn, A.K., I. Rosenwaike, N. Hermann, P. Grover, J. Stellman, and K. O'Leary. 1976. Melanoma after exposure to PCBs. N. Engl. J. Med. 295:450. 41. Baker. F.D., B. Bush, C.F. Tumasonis, and F.C. Lo. 1977. Toxicity and persistence of low-level PCB in adult Wistar rats, fetuses, and young. Arch. Environ. Contam. Toxicol. 5:143-156. 42. Bakke, J.E., V J. Feil, and A. Bergman. 1983. Metabolites of 2,4',5-trichlorobiphenyl in rats. Xenobiotica 13:555-564. 43. Ballschmiter, K. 1991. Global Distribution of Organic Compounds. Environ. Carcin. Rev. 9:1-46. 44. Ballschmiter, K., H. Buchert, and S. Bihler. 1981a. Baseline studies of global pollution. Fresenius Z. Anal. Chem. 306:323. 45. Ballschmiter, K., C. Rappe, and H.R. Buser. 1989. Chemical properties, analytical and environmental levels of PCBs, PCTs, PCNs and PCBs. In Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. R.D. Kimbrough and AA. Jensen, editors. Elsevier-North Holland, Amsterdam. 47-69. 46. Ballschmiter, K., Ch. Scholz, H. Buchert, M. Zell, K. Figge, K. Polzhofcr. and H. Hoerschelmann. 1981b. Studies of the global baseline pollution. Fresenius Z. Anal. Chem. 309:1-7. 47. Ballschmiter, K. and M. Zell. 1980. Analysis of polychlorinated biphenyls (PCB) by glass capillary gas chromatography. Composition of technical Aroclor- and Clophen-PCB mixtures. Fresenius Z. Anal. Chem. 302:20-31. 48. Bandiera, S., K. Farrell, G. Mason, M. Kelley, M. Romkes, R. Bannister, and S. Safe. 1984. Comparative toxicities of the polychlorinated dibenzofuran (PCDF and biphenyl (PCB) mixtures which persist in Yusho victims. Chemosphere 13:507-512. 57 49. Bandiera, S., S. Safe, and A.B. Okey. 1982. Binding of polychlorinaled biphenyls classified as cither phenobarbitone-, 3-methylcholanthrene-, or mixed-type inducers to cytosolic Ah receptor. Chem. -Bioi. Interact. 39:259-277. 50. Bannister, R., D. Davis, T. Zacharewski, I. Tizard, and S. Safe. 1987a. Aroclor 1254 as a 2,3,7,8- tetrachlorodibenzo-p-dioxin antagonist: effects on enzyme activity and immunotoxicity. Toxicology 46:29-42. 5 1 . Bannister, R. and S. Safe. 1987b. Synergistic interactions of 23,7,8-TCDD and 2,2',4,4',5,5'-hexachlorobiphenyl in C57BL/6J and DBA/2J mice: role of the Ah receptor. Toxicology 44:159-169. 52. Barnes, D.G. 1991. Toxicity equivalents and EPA's risk assessment of 2,3,7,8-TCDD. Sci. Total Environ. 104:73-86. 53. Barsotti, DA. and J.R. Alien. 1975. Effects of polychlorinated biphenyls on reproduction in the primate. Fed. Proc. 34:338. 54. Barsotti, D.A., R J. Marlar, and J.R. Alien. 1976. Reproductive dysfunction in rhesus monkeys exposed to low levels of polychlorinated biphenyls (Aroclor 1248). Food Cosmet. Toxicol. 14:99-103. 55. Bastomsky, C.H. 1974. Effects of a polychlorinated biphneyls mixture (Aroclor 1254) and DOT on biliary thyroxin excretion in rats. Endocrinol. 95:1150-1155. 56. Baumann, M., E. Deml, E. Schaffer, and H. Greim. 1983. Effects of polychlorinated biphenyls at low dose levels in rats. Arch. Environ. Contam. Toxicol. 12:509-515. 57. Beck, H., A. Dross, and W. Mathar. 1992. PCDDs, PCDFs, and related contaminants in the German food supply. Chemosphere 25:1539-1550. 58. Becker, G.M., W.P. McNulty, and M. Bell. 1979. Polychlorinated biphenyl-induced morphologic changes in the gastric mucosa of the rhesus monkey. Laboratory Investigation 40:373-383. 59. Becker, M.M. and W. Gamble. 1982. Determination of the binding of 2,4,5,2',4',5'-hexachlorobiphenyl by low density lipoprotein and bovine serum albumin. /. Toxicol. Environ. Health 9:225-234. 60. Beebe, L.E., S.D. Fox, H J. Issaq, and L.M. Anderson. 1991. Biological and biochemical effects of retained polyhalogenated hydrocarbons. Environ. Toxicol. Chem. 10:757-763. 61. Beebe, LE^ S.D. Fox, C.W. Riggs, S.S. Park, H.V. Gelboin, H J. Issaq, and L.M. Anderson. 1992. Persistent effects of a single dose of Aroclor 1254 on cytochromes P450IA1 and IIB1 in mouse lung. Toxicol. Appi. PharmacoL 114:16-24. 62. Bellin, J.S. and D.G. Barnes. 1989. Interim Procedures for Estimating Risks Associated with Exposures to Mixtures of Chlorinated Dibenzo-p-Dioxins and -Dibenzofurans (CDDs and CDFs). United States Environmental Protection Agency, Washington, D.C.. 63. Bergman, A., A. Biessmann, I. Brandt, and J. Rafter. 1982. Metabolism of 2,4,5-trichlorobiphenyl: role of the intestinal microflora in the formation of bronchial-seeking methylsulphone metabolites in mice. Chem. -Biol. Interact. 40:123-131. 64. Bergman, A^ I. Brandt, and B. Jansson. 1979. Accumulation of methylsulfonyl derivatives of some bronchial- seeking polychlorinated biphenyls in the respiratory tract of mice. Toxicol. Appl. PharmacoL 48:213-220. 58 (>5. Bergman, A., I. Brandt, P.O. Barnerud and C.A. Wachtmeistcr. 1982. Metabolism of 2,2'.5,5'- tetrachlorobiphenyl: formation of mono- and bis-methyl sulphone metabolites \vith a selective affinity for the lung and kidney tissues in mice. Xenobiotica 12:1-7. 66. Bergman, A., M. Athanasiadou, S. Bergek, K. Haraguchi, S. Jensen, and E. Klasson Wehler. 1992. PCB and PCB methyl sulphones in mink treated with PCB and various PCB fractions. Ambio 21:570-576. 67. Bergman, A., B-M. Backlin, B. Jarplid. L. Grimelius, and E. Wilander. 1992. Influence of commercial polychlorinated biphenyls and fractions thereof on liver histology in female mink (Mustela vison). Ambio 21:591-595. 68. Berry, D.L., J. DiGiovanni, M.R. Juchau, W.M. Bracken, G.L. Gleason, and TJ. Slaga. 1978. Lack of tumor-promoting ability of certain environmental chemicals in a two-stage mouse skin tumorigenesis assay. Res. Comm. Chem. Pathol. Phamacol. 20:101-107. 69. Berry, D.L., T.J. Slaga, J. DiGiovanni, and M.R. Juchau. 1979. Studies with chlorinated dibenzo-/7-dioxins, polybrominated biphenyls, and polychlorinated biphenyls in a two-stage system of mouse skin tumorigenesis: potent anticarcinogenic effects. Ann. N. Y. Acad. Set. 320:405-414. 70. Bertazzi, PA., L. Ribaldi, A. Pesatori, L. Radice, and C. Zocchetti. 1987. Cancer mortality of capacitor manufacturing workers. Am. J. Ind. Med. 11:165-176. 71. Biegel, L., M. Harris, D. Davis, R. Rosengren, L. Safe, and S. Safe. 1989.2,2',4,4',5,5'-Hexachlorobiphenyl as a 2^,7,8-tetrachlorodibenzo-p-dJoxin antagonist in C57BL/6J mice. Tended. AppL Pharmacoi 97:561-571. 72. Biocca, M., B.N. Gupta, K. Chae, J.D. McKinney, and J A. Moore. 1981. Toricity of selected symmetrical hexachlorobiphenyl isomers in the mouse. Taxicol. Appl. Pharmacoi. 58:461-474. 73. Birnbaum, LJS. 1992. EPA's reassessment of dioxin risk; directed health effects. Organohalogen Compounds, Dioxin '92 10:287-290. 74. Birnbaum, L.S. and M.B. Baird. 1978. Induction of hepatic mixed function oxidases in senescent rodents. Exp. Geront. 13:299-303. 75. Birnbaum, L.S., M.W. Harris, D.D. Crawford, and R.E. Morrissey. 1987. Teratogenic effects of polychlorinated dibenzofurans in combination in C57BL/6N mice. Toxicol. Appl. Pharmacoi. 91:246-255. 76. Bleavins, M.R., R J. Aulerich, and R.K. Ringer. 1980. Polychlorinated biphenyls (Aroclors 1016 and 1242): effects on survival and reproduction in mink and ferrets. Arch. Environ. Contam. Toxicol. 9:627-635. 77. Blomkvist, G., A. Roos, J. Jensen, A. Bignert, and M. Olsson. 1992. Concentrations of sDDT and PCB in seals from Swedish and Scottish waters. Ambio 21:539-545. 78. Boobis, A.R., D.W. Nebert, and O. Pelkonen. 1979. Effects of microsomal enzyme inducers in vivo and inhibitors in vitro on the covalent binding of benzo[a]pyrene metabolites to DNA catalized by liver microsomes from genetically responsive and nonresponsive mice. Biochem. Pharmacoi. 28:111-121. 79. Borlakoglu, J.T., S. Clarke, S-W. Huang, R.R. Kils, K.D. Haegele. and G.G. Gibson. 1992. Lactational transfer of 3,3',4,4'-tetrachloro- and 2,2',4,4',5, 5'-hexachlorobiphenyl induces cytochrome P450IVA1 in neonates: evidence for a potential synergistic mechanism. Biochem. Pharmacoi. 43:153-157. 80. Borlakoglu, J.T., J.D. Edwards-Webb, and R.R. Dils. 1990a. Polyclorinated biphenyls increase fatty acid desaturation in the proliferating endoplasmic reticulum of pigeon and rat livers. Ear. J. Biochem. 188:327-332. 59 81. Borlakoglu, J.T., J.D. Edwards-Webb, R.R. Oils, J.P.G. Wilkins, and L.W. Robertson. 1989. Evidence for the induction of cytochromes P-452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls. FEBS Letters 247:327-329. 82. Borlakoglu, J.T., J.P.G. Wilkins, C.H. Walker, and R.R. Oils. 1990b. Polychlorinated biphenyls (PCBs) in fish-eating sea birds. II. Molecular features of PCB isomers and congeners in adipose tissue of male and female puffins (Fratercula arctica), guillemots (Una aalga), shags (Phalacrocorax aristotelis) and cormorants (Phalacrocorax carbo) of British and Irish coastal waters. Comp. Biochem. Physiol. 97:161-171. 83. Borlakoglu, J.T., J.P.G. Wilkins, C.H. Walker, and R.R. Oils. 1990c. Polychlorinated biphenyls (PCBs) in fish-eating sea birds. III. Molecular features and metabolic interpretations of PCB isomers and congeners in adipose tissues. Comp. Biochem. Physiol. 97:173-177. 84. Borlakoglu, J.T., J.P.G. Wilkins, C.H. Walker, and R.R. Oils. 1990d. Polychlorinated biphenyls (PCBs) in fish-eating sea birds -1. Molecular features of PCB isomers and congeners in adipose tissue of male and female razorbills (Alca tardd) of British and Irish coastal waters. Comp. Biochem. Physiol. 97:151-160. 85. Bosveld, BA.T.C, M. Van den Berg, and R.M.C. Theelen. 1992. Assessment of the EROD inducing potency of eleven 23,7,8-substituted PCDD/Fs and three coplanar PCBs in the chick embryo. Chemosphere 25:911-916. 86. Botelho, L.H., D.E. Ryan, and W. Levin. 1979. Amino acid compositions and partial amino acid sequences of three highly purified forms of liver microsomal cytochrome P-450 from rats treated with polychlorinated biphenyls, phenobarbital, or 3-methylcholanthrene. /. Biol. Chem. 254:5635-5640. 87. Bowes, G.W., M J. Mulvihill, M.R. DeCamp, and A.S. Kende. 1975a. Gas chromatographic characteristics of authentic chlorinated dibenzofurans: identification of two isomers in American and Japanese polychlorinated biphenyls. /. Agr. Food Chem. 23:1222. 88. Bowes, G.W., M J. Mulvihill, B.R.T. Simoneit, A.L. BurUngame, and R.W. Risebrough. 1975b. Identification of chlorinated dibenzofurans in American polychlorinated biphenyls. Nature 256:305-307. 89. Bowman, R.E., M.P. Heironimus, and J.R. Alien. 1978. Correlation of PCB body burden with behavioral toxicology in monkeys. Pharmacol. Biochem. Behav. 9:49-56. 90. Bowman, R.E., MJ*. Heironimus, and DA. Barsotti. 1981. Locomotor hyperactivity in PCB-exposed rhesus monkeys. Neurotcadcoloiy 2:251-268. 91. Bradlaw, JA. and J.L. Casterline,Jr.. 1979. Induction of enzyme activity in cell culture: a rapid screen for detection of planar polychlorinated organic compounds. /. Assoc. Offic. Anal. Chem. 62:904-916. 92. Brandt, I. and A. Bergman. 1981. Bronchial mucosal and kidney cortex affinity of 4- and 4,4'-substituted sulphur-containing derivatives of 2,2',5,5'-tetrachlorobipheuyl in mice. Chem. -Biol. Interact. 34:47-55. 93. Brandt, I., P.O. Darnerud, A. Bergman, and Y. Larsson. 1982a. Metabolism of 2,4',5-trichlorobiphenyl: enrichment of hydroxylated and methyl sulphone metabolites in the uterine luminal field of pregnant mice. Chem. -Biol. Interact. 40:45-56. 94. Brandt, I., E. Klasson-Wehler, J. Rafter, and A. Bergman. 1982b. Metabolism of 2,4',5-trichlorobiphenyl: tissue concentrations of methyisulphonyi-2,4',5-trichlorobiphenyl in germfree and conventional mice. Taxicol. Lett. 12:273-280. 60 95. Branch. I., J. Lund, A. Bergman, E. Klasson-Wehler, L. Poellinger, and J-A. Gustafsson. 1985. Target cells for the polychlorinated biphenyl metabolite 4,4'-bis(methylsulfonyl)-2,2',5.5'-telrachlorobiphenyl in lung and kidney. Drug Metab. Disp. 13:490-496. 96. Brouwer. A., E. Klasson-Wehler, M. Bokdam, D.C. Morse, and WA. Traag. 1990. Competitive inhibition of thyroxin binding to transthyretin by mono-hydroxy metabolites of 3,43',4'-tetrachlorobiphenyl. Oiemosphere 20:1257-1262. 97. Brouwer, A., A. Kukler, and KJ. Van den Berg. 1988. Alterations in retinoid concentrations in several extrahepatic organs of rats by 3,4,3',4'-tetrachlorobiphenyl. Toxicology 50:317-330. 98. Brouwer, A. and KJ. Van den Berg. 1984. Early and differential decrease in natural retinoid levels in C57BL/Rij and DBA/2 mice by 3,4,3',4'-tetrachlorobiphenyl. Toxicol. Appl. Pharmacol. 73:204-209. 99. Brouwer, A. and KJ. Van den Berg. 1986. Binding of a metabolite of 3,4,3',4'-tetrachlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein com plex carrying both retinol and thyroxin. Toxicol. Appl. Pharmacol. 85:301-312. 100. Brouwer, A., KJ. Van den Berg, and A. Kukler. 1985. Time and dose responses of the reduction in retinoid concentrations in C57BL/Rij and DNA/2 mice induced by 3,4,3',4'-tetrachlorobiphenyl. Toxicol. Appl. Pharmacol. 78:180-189. 101. Brown, D.P. 1987. Mortality of workers exposed to polychlorinated biphenyls - an update. Arch. Environ. Health 42:333-339. 102. Brown, D.P. and M. Jones. 1981. Mortality and industrial hygiene study of workers exposed to polychlorinated biphenyls. Arch. Environ. Health 36:120-129. 103. Bruckner, J.V., W-D. Jiang, J.M. Brown, L. Putcha, C.K. Chu, and VJ. Stella. 1977. The influence of ingestion of environmentally encountered levels of a commercial polychlorinated biphenyl mixture (Aroclor 1254) on drug metabolism in the rat. /. Pharmacol. Exp. Ther. 202:22-31. 104. Bruckner, J.V., K.L. Khanna, and H.H. Cornish. 1973. Biological responses of the rat to polychlorinated biphenyls. Toxicol. Appl. Pharmacol. 24:434-448. 105. Bruckner, J.V., K.L. Khanna, and H.H. Cornish. 1974a. Polychlorinated biphenyl-induced alteration of biologic parameters in the rat. Toxicol. Appl. Pharmacol. 28:189-199. 106. Bruckner, J.V., K.L. Khanna, and H.H. Cornish. 1974b. Effect of prolonged ingestion of polychlorinated biphenyls on the rat. Food Cosmet. Toxicol. 12:323-330. 107. Brunn, H., E. Schmidt, M. Reinacher, D. Manz, and E. Eigenbrodt. 1987. Histology and histochemistry of the liver of chickens after DENA induced hepatocarcinogenesis and ingestion of low chlorinated biphenyls. Arch. Toxicol. 60:337-342. 108. Brunstrom, B. 1986. Activities in chick embryos of 7-ethoxycoumarin O-deethylase and aryl hydrocarbon (benzo[a]pyrene) hydroxyiase and their induction by 33',4,4'-tetrachlorobiphenyl in early embryos. Xenobiotica 16:865-872. 109. Brunstrom, B. 1990a. Mono-o/f/io-chlorinated chlorobiphenyls: toxicity and induction of 7-ethoxyresorufin O-deethylase (EROD) activity in chick embryos. Arch. Toxicol. 64:188-192. 110. Brunstrom, B. 1992a. Embryolethality and induction of 7-ethoxyresorufin O-deethylase in chick embryos 61 by polychJorinated biphenyls and polycyclic aromatic hydrocarbons having Ah receptor affinity. Chem. Biol. Interact. 81:69-77. 111. Brunstrom. B. 1992b. Induction of cytochrome P-450-dependent enzyme activities in female mink (Musiela vison) and their kits by technical PCB preparations and fractions thereof. Ambto 21:585-587. 112. Brunstrom, B., L. Andersson, E. Nikolaidis, and L. Dencker. 1990b. Non-ort/io- and mono-ort/io-chlorine- substituted polychlorinated biphenyis - embryotoxicity and inhibition of lymphoid development. Chemosphere 20:1125-1128. 113. Brunstrom, B. and P.O. Darnerud. 1983. Toxicity and distribution in chick embryos of 3,3',4,4'- tetrachlorobiphenyl injected into the eggs. Toxicology 27:103-110. 114. Brunstrom, B., H. Hakansson, and K. Lundberg. 1991. Effects of a technical PCB preparation and fractions thereof on ethoxyresorufin O-deethylase activity, vitamin- A levels and thymic development in the mink (Musteia vison). Pharmacol. Toxicol. 69:421-426. 115. Brunstrom, B , I. Kihlstrom, and U. Lundkvist. 1982. Studies of fetal death and fetal weight in guinea pigs fed polychlorinated biphenyls (PCB). Acta Pharmacol. Toxicol. 50:100-103. 116. Buchmann, A., W. Kunz, C.R. Wolf, F. Oesch, and L.W. Robertson. 1986. Polychlorinated biphenyls, classified as either phenobarbital-or 3-methylcholanthrene-type inducers of cytochrome P-450, are both heptic tumor promoters in diethylnitrosamine-initiated rats. Cancer Lett. 32:243-253. 117. Buchmann, A., S. Ziegler, A. Wolf, L.W. Robertson, S.K. Durham, and M. Schwarz. 1991. Effects of polychlorinated biphenyls in rat liver: correlation between primary subcellular effects and promoting activity. Toxicol. Appi. Pharmacol. 111:454-468. 118. Bunyan, PJ. and J.MJ. Page. 1978. Polychlorinated biphenyls. The effect of structure on the induction of quail hepatic microsomal enzymes. Toxicol. Appl. Pharmacol. 43:507-518. 119. Buser, H.R., C. Rappe, and A. Gara. 1978. Polychlorinated dibenzofurans (PCDFs) found in Yusho oil and in used Japanese PCB. Chemosphere 5:439-449. 120. Bush, B., R.W. Streeter, and R J. Sloan. 1989. Polychlorobiphenyl (PCB) congeners in striped bass (Morone saxadlis) from marine and estuarine waters of New York State determined by capillary gas chromatography. Arch. Environ. Contam. Toxicol. 19:49-61. 121. Byrne, J J., J.P. Carbone, and E.A. Hanson. 1987. Hypothvroidism and abnormalities in the kinetics of thyroid hormone metabolism in rats treated chronically with polychlorinated biphenyl and polybrominated biphenyl. Endocrinol. 21:520-527. 122. Byrne, J J., J.P. Carbone, and M.G. Pepe. 1988. Suppression of serum adrenal cortex hormones by chronic low-dose polychlorobiphenyl or polybromobiphenyl trealments./4/c/i. Environ. Contam. Toxicol. 17:47-i3. 123. Carter, J.W. and L.P. Mercer. 1983. Prediction of food intake, weight gain and organ weights in rats as a formulation of dietary Aroclor 1254 (PCBs) by the saturation kinetics model for physiological responses. Nutr. Rep. Int. 27:561-568. 124. Chase, K.H., O. Wong, D. Thomas, B.W. Stal, B.W. Berney, and R.K. Simon. 1982. Clinical and metabolic abnormalities associated with occupational exposure to polychlorinated biphenyls./. Occup. Med. 24:109-114. 125. Chen, L-C, I. Berberian, B. Koch, M. Mercier, V. Azais-Braesco, H.P. Glauert, C.K. Chow, and L.W. 62 Robertson. 1992a. Polychlorinated and polybrominated biphenyi congeners and retinoid levels in rat tissues: structure-activity relationships. Toxicol. Appl. Pharmacol. 114:47-55. 126. Chen, P.H., K.T. Chang, and Y.D. Lu. 1981. Polychlorinated biphenyls and polychlorinated dibenzofurans in the toxic rice-bran oil that caused PCB poisoning in Taichung. Bull. Environ. Contam. Toxicol. 26:489^*95. 127. Chen, P.H., Y.D. Lu, M.H. Yang, and J.S. Chen. 1981. Toxic compounds in the cooking oil which caused PCB poisoning in Taiwan. II. The presence of polychlorinated quaterphenyls and polychlorinated terphenyls (in Chinese). Clin. Med. 7:77-82. 128. Chen. Y-CJ., Y-L. Guo, C-C. Hsu, and WJ. Rogan. 1992b. Cognitive development of Yu-Chcng ("oil disease") children prenatally exposed to heat-degraded PCBs. /. Amer. Med. Assoc. 268:3213-3218. 129. Chou, S.M., T. Miike, W.M. Payne, and G J. Davis. 1979. Neuropathology of "spinning syndrome" induced by prenatal intoxication with a PCB in mice. Ann. N. Y. Acad. Set. 320:373-395. 130. Chu, C.K., V J. Stella, J.V. Bruckner, and W.D. Jiang. 1977. Effects of long-term exposure to environmental levels of polychlorinated biphenyls on pharmacokinetics of pentobarbital in rats./. Pharm. Sci. 66:238-241. 131. Clark, DA., G. Sweeney, S. Safe, E. Hancock, D.G. Kilburn, and J. Gauldie. 1983. Cellular and genetic basis for suppression of cytotoxic T cell generation by haloaromatic hydrocarbons. Immunopharmacol. 6:143-153. 132. Collins, W.T. and C.C. Capen. 1980a. Biliary excretion of thyroxine-1-125 and fine structural alterations in the thyroid glands of gunn-rats fed PCBs. Lab. Invest. 43:158-164. 133. Collins, W.T. and C.C. Capen. 1980b. Ultrastructural and functional alterations of the rat thyroid gland produced by polychlorinated biphenyls compared with iodide excess and deficiency, and thyrotropin and thyroxine administration. Vmhows Arch. 33:213-231. 134. Collins, W.T., C.C. Capen, L. Kasza, C. Carter, and R.E. Dailey. 1977. Effect of polychlorinated biphenyls (PCB) on the thyroid gland of rats. Am. J. Pathol. 89:119-130. 135. Conney, A.H. 1967. Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev. 19:317- 366. 136. Conney, A.H. 1982. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res. 42:4875-4917. 137. Corbett, J., P.W. Albro, K. Chae, and S. Jordan. 1982. The relationship between metabolism of 2^,4,53',4',5'- heptachlorobiphenyl and its ability to induce both cytochromes P-448 and P-450. Chem. -Biol. Interact. 39:331-338. 138. Davidorf, F.H. and J A. Knupp. 1979. Epidemiology of ocular melanoma, incidence and geographical relationship in Ohio (1967 - 1977). Ohio State Med. J. 75:561. 139. Davis, D. and S. Safe. 1989. Dose-response immunotoxicities of commercial polychlorinated biphenyls (PCBs) and their interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Lett. 48:35-43. 140. Davis, D. and S. Safe. 1990. Immunosuppressive activities of polychlorinated biphenyls in C57BL/6 mice: structure-activity relationships as Ah receptor agonists and partial antagonists. Toxicol. 63:97-111. 141. De Jongh, J., F. Wondergem, W. Seinen, and M. Van den Berg. 1992. Absence of interactions on hepatic 63 retention and 7-ethoxyresomfin-O-deethylalion activity after co-administration of 1,23.7,8-pentachlorodibenzo- /7-dioxin and 2,4,5,2',4',5'-hexachlorobiphenyl. Toxicology 75:21-28. 142. De Voogt, P. and U-A.T. Brinkman. 1989. Production, properties and usage of polychlorinated biphenyls. In Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. R.D. Kimbrough and A.A. Jensen, editors. Elsevier - North Holland, Amsterdam. 3-45. 143. Deml, E. and D. Oesterle. 1982. Sex-dependent promoting effect of polychlorinated biphenyls on enzyme- altered islands induced by diethylnitrosamine in rat liver. Carcinogenesis 3:1449-1453. 144. Deml, E., D. Oesterle, and FJ. Wiebel. 1983. Benzo[a]pyrene initiates enzyme-altered islands in the liver of adult rats following single pretreatment and promotion with polychlorinated biphenyls. Cancer Lett. 19:301-304. Deml, E. and D. Oesterle. 1986. Enhancing effect of co-administration of polychlorinated biphenyls and diethylnitrosamine on enzyme-altered islands induced by diethylnitrosamine in rat liver. Carcinogenesis 7:1697-1700. 145. Denomme, MA., S. Bandiera, I. Lambert, L. Copp, L. Safe, and S. Safe. 1983. Polychlorinated biphenyls as phenobarbitone-type inducers of microsomal enzymes - structure activity relationships for a series of 2,4-dichloro-substituted congeners. Blochem. Pharmacol. 32:2955-2963. 146. Denomme, M.A., B. Leece, A. Li, R. Towner, and S. Safe. 1986. Elevation of 23,7,8-tetrachlorodibenzo-/>- dioxin (TCDD) polychlorinated biphenyls: structure-activity relationships. Biochem. PharmacoL 35:277-282. 147. De Vito, M J., W.E. Maier, J J. Diliberto and L.S. Birnbaum. 1993. Comparative ability of various PCBs, PCDFs and TCDD induce cytochrome P450 1A1 and LA2 activity following weeks of treatment. Fund. Appl. Toxicoi. 20:125-130. 148. Dewailly, E., J.P. Weber, S. Gingras, and C. Laliberte. 1991. Coplanar PCBs in human milk in the province of Quebec, Canada -are they more toxic than dioxin for breast fed infants. Bull. Environ. Contain. Toxicoi. 47:491-498. 149. Dogra, S., J.G. Filser, C. Cojocel, H. Greim, U. Regel, R. Oesch, and L.W. Robertson. 1988. Long-term effects of commercial and congeneric polychlorinated biphenyls on ethane production and malondialdehyde levels, indicators in in vivo lipid peroxidation. Arch. Toxicoi. 62:369-374. 150. Duarte-Davidson, R., V. Burnett, K.S. Waterhouse, and K.C. Jones. 1991. A congener specific method for the analysis of polychlorinated biphenyls (PCBs) in human milk. Chemospnere 23:119-131. 151. Eadon, G., L. Kaminsky, J. Silkworth, K. Aldous, D. Hilker, P. O-Keefe, R. Smith, J.F. Gierthy, J. Hawley, N. Kim, and A. DeCaprio. 1986. Calculation of 2,3,7,8-TCDD equivalent concentrations of complex environmental contaminant mixtures. Environ. Health Perspect. 70:221-227. 152. Ebner, K.V. and W.E. Braselton. 1987. Structural and chemical requirements of hydroxylated polychlorinated biphenyls (PCBOH) for inhibition of energy-dependent swelling of rat liver mitochondria. Chem. -Biol. Interact, 63:139-155. 153. Ecobichon, D J. 1975. The influence of polychlorinated biphenyl compounds on the hepatic function in the rat. Environ. Sci. Res. 7:207-214. 154. Ecobichon, D J. and D.O. MacKenzie. 1974. The uterotropic activity of commercial and isomerically-pure chlorobiphenyls in the rat. Res. Comm. Chem. Pathol. Pharmacol. 9:85-95. 155. Edqvist, L-E., A. Made], and M. Forsberg. 1992. Biochemical blood parameters in pregnant mink fed 64 PCB and fractions of PCB. Ambio 21:577-581. 156. Egaas, E. and U. Varanasi. 1982. Effects of polychlorinatcd biphenyls and environmental temperature on in \.itro formation of bcnzo[a]pyrene metabolites by liver of trout (Salmo gairdrteri}. Biochem. Pharmacol. 31:561-566. 157. Elcombe, C.R. and JJ. Lech. 1979. Induction and characterization of hemoprotein(s) P-450 and monoxygenation in rainbow trout (Salmo gairdneri). Toxicol. Appl. Pharmacol. 49:437-450. 158. Elliott, J.E., S.W. Kennedy, D. Jeffrey, and L. Shutt. 1991. Polychlorinated biphenyl (PCB) effects on hepatic mixed function oxidases and porphyria in birds. II. American kestrel. Comp. Biochem. Physiol. 99:141-145. 159. Emmett, E_A. 1985. Polychlorinated biphenyl exposure and effect in transformer repair workers. Environ. Health Perspect. 60:185-192. 160. Emmett, E_A., M. Maroni, J. Jefferys, J. Schmith, B.K. Levin, and A. Alvares. 1988. Studies of transformer repair workers exposed to PCBs: II. Results of clinical laboratory investigations. Am. J. Ind. Med. 14:47-62. 161. Eriksson, P. 1988. Effects of 3,3',4,4'-tetrachJorobiphenyl in the brain of the neonatal mouse. Toxicology 49:43-48. 162. Eriksson, P., U. Lundkvist, and A. Fredriksson. 1991. Neonatal exposure to 3,3'A4'-tetrachlorobiphenyl: changes in spontaneous behaviour and cholinergic muscarinic receptors in the adult mouse. Toxicology 69:27-34. 163. Evans, M.S., G.E. Noguchi, and C.P. Rice. 1991. The biomagnification of polychlorinated biphenyls, toxaphene, and DDT compounds in a Lake Michigan offshore food web. Arch. Environ. Contain. Toxicol. 20:87-93. 164. Exon, J.H., PA. Talcott, and L.D. Koller. 1985. Effect of lead, polychlorinated biphenyls, and cyclophosphamide on rat natural killer cells, interleukin 2, and antibody synthesis. Fund. Appl. Toxicol. 5:158-164. 165. Fait, A., E. Grossman, S. Self, J. Jeffries, E.D. Pellizzari, and E A. Emmett. 1989. Polychlorinated biphenyl congeners in adipose tissue lipid and serum of past and present transformer repair workers and a comparison group. Fund. Appl. Toxicol. 12:42-55. 166. Falck, F., A. Ricci, M.S. Wolff, J. Godbold, and P. Deckers. 1992. Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer. Arch. Environ. Health 47:143-146. 167. Farland, W.H. and J.L. Schaum. 1992. EPA's reassessment of dioxin health effects and approaches to estimating exposure. Organohalogen Compounds, Dioxin '92 10:311-312. 168. Fein, G.G., J.L. Jacobson, S.W. Jacobson, P.M. Schwartz, and J.K. Dowler. 1984. Prenatal exposure to polychlorinated biphenyls: effects on birth size and gestational age. /. Pediatr. 105:315-320. 169. Fischbein, A. 1985. Liver function tests in workers with occupational exposure to polychlorinated biphenyls (PCBs): comparison with Yusho and Yu Cheng. Environ. Health Perspect. 60:145-150. 170. Fishbein, L. 1972. Chromatographic and biological aspects of polychlorinated biphenyls. /. Chromatogr. 68:345. 171. Fitzgerald, E.F., A.L. Weinstein, L.G. Youngblood, S J. Standfast, and J.M. Melius. 1989. Health effects 65 three years after potential exposure to the toxic contaminants of an electrical transformer fire. Arch. Emimn. Health 44:214-221. 172. Flodstrom, S. and U.G. Ahlborg. 1992. Relative liver tumor promoting activity of some polychlorinated dibenzo-p-dioxin-, dibenzofuran- and biphenyl-congeners in female rats. Chemosphere 25:169-172. 173. Forlin, L. 1980. Effects of Clophen A50, 3-methylcholanthrene, prenenolone-16a-carbonilrile, and phenobarbital on the hepatic microsomal cytochrome P-450-dependent monooyxygenase system in rainbow trout, Salmo gairdneri, of different age and sex. Toxicol. Appl. Pharmacol. 54:420-430. 174. Forlin, L. and U. Lidman. 1978. Effects of Clophen A50,4-, 2^^'4'-tetra- and 2,4r5,2',4',5'-hexachlorobiphenyl on the mixed-function oxidase system of rainbow trout (Salmo gairdnerii Rich.) liver. Comp. Biochem. Physiol. 60:193-197. 175. Fossi, C, C. Leonzio, S. Focardi, and A. Renzoni. 1988. Seasonal variations in aldrin epoxidase (MFO) activity of yellow-legged herring gulls: the relationship to breeding and PCB residues. BulL Environ. Contatn. Toxicol. 41:365-370. 176. Fysh, J.M. and A.B. Okey. 1978. Aryl hydrocarbon (benzo[a]pyrene) hydroxylase development in rat mammary tissue. Biochem. Pharmacol. 27:2968-2972. 177. Garthoff, L.H., L. Friedman, T.M. Farber, K.K. Locke, T J. Sobotka, S. Green, N.E. Hurley, E.L. Peters, G.E. Story, P.M. Moreland, C.H. Graham, J.E. Keys, M J. Taylor, J.V. Scalera, J.E. Rothlein, E.M. Marks, F.E. Cerra, S.B. Rodi, and E.M. Sporn. 1977. Biochemical and cytogenetic effects in rats caused by short-term ingestion or Aroclor 1254 or Firemaster BP6. /. Toxicol. Environ. Health 3:769-7%. 178. Gellert, R J. 1978. Uterotrophic activity of polychlorinated biphenyls (PCB) and induction of precocious reproductive aging in neonatally treated female rats. Environ. Res. 16:123-130. 179. Ghazarian, J.G., J.E. Martinez, A.C. Gallardo, J A. Kulkoski, and B.L. Peterson. 1980. Induction of renal cytochrome P-450 by the polychlorinated biphenyl Aroclor-1254. /. Biol. Chem. 255:8275-8281. 180. Gillette, D.M., R.D. Corey, W.G. Helferich, J.M. McFarland, LJ. Lowenstine, D.E. Moody, B.D. Hammock, and L.R. Shull. 1987. Comparative toxicology of tetrachlorobiphenyls in mink and rats. I. Changes in hepatic enzyme activity and smooth endoplasmic reticulum volume. Fund. Appl. Toxicol. 8:5-14. 181. Gillner, M., J. Lund, C. Cambillau, M. Alexandersson, U. Hurlig, . Bergman, E. Klasson-Wehler, and J-. Gustafsson. 1988. The binding of methylsulfonyl-polychloro-biphenyls to uteroglobin. /. Steroid Biochem. 31:27-33. 182. Gladen, B.C. and WJ. Rogan. 1991. Effects of perinatal polychlorinated biphenyls and diclorodiphenyl dichloroethene on later development. /. Pediatr. 119:58-63. 183. Gladen, B.C., WJ. Rogan, P. Hardy, J. Thulen, J. TingeUad, and M. Tully. 1988. Development after exposure 184. Goldman, D. and A. Yawetz. 1990. The interference of Aroclor 1254 with progesterone metabolism in guinea pig adrenal and testes microsomes. /. Biochem. Toxicol. 5:99-107. 185. Goldman, D. and A. Yawetz. 1991. Cytochrome P-450 mediated metabolism of progesterone by adrenal microsomes of PCB-treated and untreated barn owl (Tyto alba and marsh turtle (Mauremys caspica) in comparison with the guinea-pig. Comp. Biochem. Physiol. 99:251-255. 66 186. Goldman, D. and A. Yawetz. 1992. The interference of polychlorinated biphenyls (Aroclor 1254) with membrane regulation of the activities of cytochrome-P-450C21 and cytochrome-P-45017<1|VMC in guinea-pig adrenal microsomes. /. Steroid Biochem Mol. Biol. 42:37-47. 187. Goldstein, J., P. Linko, J.D. McKinney, and P.W. Albro. 1981. Marked differences in the inductive effects of two symmetrical hexachlorobiphenyls and the corresponding unsymmetrical isomer on hepatic monooxygenases. Biochem. Pharmacol. 30:1008-1011. 188. Goldstein, J A., J.R. Haas, P. Linko, and D J. Harvan. 1978.23,7,8-Tetrachlorodibenzofuran in a commercially available 99% pure polychlorinated biphenyl isomer identified as the inducer of hepatic cytochrome P-448 and aryl hydrocarbon hydroxylase in the rat. Drug Metab. Dispos. 6:258-264. 189. Goldstein, JA., P. Hickman, H. Bergman, J.D. McKinney, and M.P. Walker. 1977. Separation of pure polychlorinated biphenyl isomers into two types of inducers on the basis of induction of cytochrome P-450 or P-448. Chem. -Biol. Interact. 17:69-87. 190. Goldstein, J A., P. Hickman, V.W. Burse, and H. Bergman. 1975. A comparative study of two polychlorinated biphenyl mixtures (Aroclors 1242 and 1016) containing 42% chlorine on induction of hepatic porphyria and drug metabolizing enzymes. Toxicol. Appl. Pharmacol. 32:461-473. 191. Goldstein, JA., P. Linko, M.I. Luster, and D.W. Sundheimer. 1982. Purification and characterization of a second form of hepatic cytochrome P-448 from rats treated with a pure polychlorinated biphenyl isomer. /. Biol. Chem. 257:2702-2707. 192. Goldstein, J A., J.D. McKinney, G.W. Lucier, P. Hickman, H. Bergman, and JA. Moore. 1976. Toxicological assessment of hexachlorobiphenyl isomers and 2,3,7,8-tetrachlorodibenzofuran in chicks. II. Effects on drug metabolism and porphyrin accumulation. Toxicol. Appl. Pharmacol. 36:81-92. 193. Goldstein, J A. and S. Safe. 1989. Mechanism of action and structure-activity relationships for the chlorinated dibenzo-p-dioxins and related compounds. In Halogenated Biphenyls, Naphthalenes, Dibenzodioxins and Related Compounds. R.D. Kimbrough and AA. Jensen, editors. Elsevier-North Holland, Amsterdam. 239-293. 194. Golub, M.S., J.M. Donald, and J A. Reyes. 1991. Reproductive toxicity of commercial PCB mixtures - LOAELs and NOAELs from animal studies. Environ. Health Penpect. 94:245-253. 195. Gonzalez, F J. and D.W. Nebert. 1985. Autoregulation plus upstream positive and negative control regions associated with transcriptional activation of the mouse cytochrome P,-450 gene. Nucleic Acids Res. 13:7269- 7288. 196. Gooch, J.W., AA. Elskus, PJ. Kloepper-Sams, M.E. Hahn, and J J. Stegeman. 1989. Effects of ortho- and non-ort/io-substituted polychlorinated biphenyl congeners on the hepatic monooxygenase system in scup (Stenotomus chrysops). Toxicol. Appl. Pharmacol. 98:422-433. 197. Graham, M J., G.W. Lucier, P. Linko, R.R. Maronpot, and J A. Goldstein. 1988. Increases in cytochrome P-450 mediated 170-estradiol 2-hydroxylase activity in rat liver microsomes after both acute administration and subchronic administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin in a two-stage hepatocarcinogenesis model. Carcinogenesis 9:1935-1941. 198. Grant, D.L. aud W.EJ. Phillips. 1974. The effect of age and sex on the toxicity of Aroclor 1254, a polychlorinated biphenyl, in the rat. Bull. Environ. Contam. Toxicol. 12:145-152. 67 199. Graves, P.E., G A. Elhag, P J. Ciaccio, D.P. Bourquc, and J.R. Halpert. 1990. cDNA and deduced ammo acid sequences of a dog hepatic cytochrome P450IIB responsible for the metabolism of 2,2',4,4',5,5'- hexachlorobiphenyl. Arch. Biochem. Biophys. 281:106-115. 200. Gray, L.E.Jr., J. Ostby, R- Marshall, and J. Andrews. 1992. Endocrine effects of a polychlorinated biphenyl mixture (Aroclor 1254): repressed sex accessory glands in hypothyroid rats with normal levels of serum and testicular testosterone. Organohalogen Compounds, Dioxin '92 10:73-76. Abstract. 201. Gregor, D J. and W.D. Gummer. 1989. Evidence of atmospheric transport and deposition of organochlorine pesticides and polychlorinated biphenyls in Canadian Arctic snow. Environ. Sci. Technol. 23:561. 202. Griffin, H., D. Windsor, and J. Borlakoglu. 1991. Changes in plasma lipoprotein metabolism in chicks in response to polychlorinated biphenyls (PCBs). Biochem. Pharmacol. 42:1493-1495. 203. Grote, W., A. Schmoldt, and H.F. Benthe. 1975a. Hepatic porphyrin synthesis in rats after pretreatment with polychlorinated biphenyls (PCBs). Acta Pharmacol. Toxicol. 36:215-224. 204. Grote, W., A. Schmoldt, and H.G. Dammann. 1975b. The metabolism of foreign compounds in rats after treatment with polychlorinated biphenyls (PCBs). Biochem. Pharmacol. 24:1121-1125. 205. Gruger, E.H.Jr., M.M. Wekell, P.T. Numoto, and D.R. Craddock. 1977. Induction of hepatic aryi hydrocarbon hydroxylase in salmon exposed to petroleum dissolved in seawater and to petroleum and polychlorinated biphenyls, separate and together, in food. Bull. Environ. Contam. Tcodcol. 17:512-520. 206. Gustavsson, P., C. Hogstedt, and C. Rappe. 1986. Short-term mortality and cancer incidence in capacitor manufacturing workers exposed to polychlorinated biphenyls (PCBs). Am. J. Ind. Med. 10:341-344. 207. Gyorkos, J., MA. Denomme, B. Leece, K. Homonko, V.E. Valli, and S. Safe. 1985. Reconstituted halogenated hydrocarbon pesticide and pollutant mixtures found in human tissues: effects on the immature male Wistar rat after short-term exposure. Can. J. Physiol. Pharmacol. 63:36-43. 208. Haake. J.M., S. Safe, K. Mayura, andT.D. Phillips. 1987. Aroclor 1254 as an antagonist of the teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Lett. 38:299-306. 209. Haake-McMillan, J.M. and S. Safe. 1991. Neonatal modulation of adult rat hepatic microsomal benzo[a]pyrene hydroxylase activities by Aroclor 1254 or phenobarbital. /. Biochem. Toxicol. 5:203-210. 210. Hakansson, H., E. Manzoor, and U.G. Ahlborg. 1992. Effects of technical PCB preparations and fractions thereof on vitamin A levels in the mink (Mustela vison). Ambio 21:588-590. 211. Hansen, L. 1987. Environmental toxicology of polychlorinated biphenyls. In Polychlorinated Biphenyls (PCBs): Mammalian and Environmental Toxicology, Environmental Toxin Series. S. Safe and O. Hutzinger, editors. Springer-Verlag Publishing Co., Heidelberg. 15-48. 212. Hansson, T., J. Rafter, and J-A. Gustafsson. 1980. Effects of some common inducers on the hepatic microsomal metabolism of androstenedione in rainbow trout with special reference to cytochrome P-450- dependent enzymes. Biochem. Pharmacol. 29:583-587. 2O. Haraguchi, K., M. Athanasiadou, A. Bergman, L. Hovander, and S. Jensen. 1992. PCB and PCB methyl sulfones in selected groups of seals from the Swedish waters. Ambio 21:546-549. 214. Haraguchi, H., K. Kuroki, Y. Masuda, and N. Shigematsu. 1984. Determination of methylthio and methylsulphone polychlorinated biphenyls in tisses of patients with "Yusho". Food Chem. TccdcoL 22:283-288. 68 215. Hardwick, J.P., P. Linko, and J A. Goldstein. 1985. Dose response for induction of two cytochrome P-450 isozymes and their mRNAs by 3,4,5,3',4',5'-hexachlorobiphenyl indicating coordinate regulation in rat liver. Mol. Pharmacol. 27:676-682. 216. Harper, N., K.Connor, and S. Safe. 1993. Comparative immunotoxic potencies of selected polychlorinated biphenyl (PCB), dibenzofuran (PCDF) and dibenzo-p-dioxin (PCDD) congeners in C57BL/6 and DBA/2 mice. Fund. Appl. Toxicol. In press. 217. Harrad, S J., A.S. Sewart, R. Boumphrey, R. Duarte-Davidson, and K.C. Jones. 1992. A method for the determination of PCB congeners 77,126 and 169 in biotic and abiotic matrices. Chemosphere 24:1147-1154. 218. Harris, M., T. Zacharewski, and S. Safe. 1993. Comparative potencies of Aroclors 1232,1242, 1248,1Z54 and 1260 in male Wistar rats - assessment of toxic equivalency factor (TEF) approach for polychlorinated biphenyls (PCBs). Fund. Appl. Toxicol. In press. 219. Harvey, G.R. and W.G. Steinhauer. 1974. Atmospheric transport of polychlorobiphenyls to the North Atlantic. Atmos. Environ. 8:777. 220. Hara, 1.1985. Health status and PCBs in blood of workers exposed to PCBs and of their children. Environ. Health Perspect. 59:85-90. 221. Hayes, MA., E. Roberts, S. Safe, E. Farber, and R.G. Cameron. 1986. Influences of different poiychlorinated biphenyls on cytocidai, mitoinhibitory, and nodule-selecting activities of ;V-2-fluorenylacetamide in rat liver. /. Natl. Cancer Inst. 76:683-691. 222. Hayes, MA., S.H. Safe, D.Armstrong, and R.G. Cameron. 1985. Influence of cell proliferation on initiating activity of pure polychJoirinated biphenyls and complex mixtures in resistant hepatocyte in vivo assays for carcinogenicity./. Natl. Cancer Inst. 71:1037-1041. 223. Hill, D.W., E. Hejtmancik, and B J. Camp. 1976. Induction of hepatic microsomal enzymes by Aroclor 1254 in Ictalurus punctatus (Channel catfish). Bull. Environ. Contam. Toxicol. 16:495-502. 224. Hinton, D.E., H. Glaumann, and B.F. Trump. 1978. Studies on the cellular toxicity of polychlorinated biphenyls (PCBs). I. Effect of PCBs on microsomal enzymes and on synthesis and turnover of microsomal and cytoplasmic lipids of rat liver - a morphological and biochemical study. Vtrchows Arch. 27:279-306. 225. Hong, C-S., B. Bush, and J. Xiao. 1992. Isolation and determination of mono-ortho and non-ortho substituted PCBs (coplanar PCBs) in human milk by HPLC porous graphite carbon and GC/ECD. Chemosphere 24:465-473. 226. Hori, S., H. Obana, T. Kashimoto, T. Otaki, H. Nishimura, M. Ikegami, N. Kunita and H. Uda. 1982. Effect of polychlorinated biphenyls and polychlorinated quaterphenyls in cynomolgus monkey (Macaco fascicularis). Toxicology 24:123-139. 227. Hornshaw, T.C., J. Safronoff, R.K. Ringer, and RJ. Aulerich. 1986. LC^ test results in polychlorinated biphenyl-fed mink: age, season, and diet comparisons. Arch. Environ. Contam. Toxicol. 15:717-723. 228. Hsu, S-T, C-I. Ma, S. Kwo-Hsiung, S.S. Wu, N.H-M. Hsu, C.C. Yeh, and S.B. Wu. 1983. Discovery and epidemiology of PCB poisoning in Taiwan: a four-year followup. Environ. Health Perspect. 59:5-10. 229. Huang, S. and G.G. Gibson. 1991. Differential induction of cytochromes P450 and cytochrome P450-dependent arachidonic acid metabolism by 3,4,5,3',4'-pentachlorobiphenyl in the rat and the guinea pig. Toxicol. Appl. 69 Pharmacol. 108:86-95. Huckins, J.N.. T.R. Schwartz, J.D. Petty, and L.M. Smith. 1988. Determination, fate, and potential significance of PCBs in fish and sediment samples with emphasis on selected AHH-inducing congeners. Chemosphere 17:1995-2016. 231. Hutton, J J., J. Meier, and C. Hackney. 1979. Comparison of the in vitro mutagenicity and metabolism of dimethylnitrosamine and benzo[a]pyrene in tissues from inbred mice treated with phenobarbital, 3- methylcholanthrene or polychlorinated biphenyls. Mutat. Res. 66:75-94. 232. Hutzinger, O., S. Safe, and V. Zitko. 1974. The Chemistry of PCBs. CRC Press, Boca Raton, FL. 233. Imaida, K., C. Furihata, M. Tatematsu, C.H. Yoon, F. Furukawa, C. Uneyama, M. TakahashL, N. Ito, and Y. Hayashi. 1991. Immunohistochemical and biochemical identification of pepsinogen isozymes in the hamster lungs: induction by polychlorinated biphenyls. Toxicol. Pathol. 19:230-236. 234. Inoue, K., A. Takanaka, K. Mizokami, K. Fujimori, M. Sunouchi, Y. Kasuya, and Y. Omori. 1981. Effects of polychlorinated biphenyls on the monooxygenase systems in fetal livers of rats. Toxicol. Appl. Pharmacol. 59:540-547. 235. International Joint Commission, 1977. LJC Great Lakes Water Quality - Appendix E, Status Report on the Persistent Toxic Pollutants in the Lake Ontario Basin. 236. Ito, N., H. Nagasaki, M. Arai, S. Makiura, S. Sugihara, and K. Hirao. 1973. Histopathologic studies on liver tumorigenesis induced in mice by technical polychlorinated biphenyls and its promoting effect on liver tumors induced by benzene hexachloride. /. Natl. Cancer Inst. 51:1637-1646. 237. Ito, N., H. Nagasaki, S. Makiura, and M. Arai. 1974. Histopathological studies on liver tumorigenesis in rats treated with polychlorinated biphenyls. Conn. 65:545-549. 238. Iverson, F., J. Truelove, and S.L. Hierlihy. 1982. Hepatic microsomal enzyme induction by Aroclors 1248 and 1254 in cynomolgus monkeys. Fa, Chem. Toxic. 20:307-310. 239. Jacob, J., G. Grimmer, G. Raab, and A, Schmoldt. 1982a. The metabolism of pyrene by rat liver microsomes and the influence of various mono-oxygenase inducers. Xenobiotica 12:45-53. 240. Jacob, J., G. Grimmer, and A. Schmoldt. 1981a. The influence of polycyclic aromatic hydrocarbons as inducers of monooxygenases on the metabolite profile of benz[a]anthracene in rat liver microsomes. Cancer Letters 14:175-185. 241. Jacob, J., A. Schmoldt, and G. Grimmer. 1981b. Time course of oxidative benz[a]anthracene metabolism by liver microsomes of normal and PCB-treated rats. Carcinogenesis 2:395-401. 242. Jacob, J., A. Schmoldt, and G. Grimmer. 1982b. Influence of monooxygenase inducers on the metabolic profile of phenanthrene in rat liver microsomes. Toxicology 25:333-343. 243. Jacob, J., A. Schmoldt, and G. Grimmer. 1982c Formation of carcinogenic and inactive chrysene metabolites by rat liver microsomes of various monooxygenase activiries. Arch. Toxicol. 51:255-265. 244. Jacob, J., A. Schmoldt, and G. Grimmer. 1983. Benzo[e]pyrene metabolism in rat liver microsomes: dependence of the metabolite profile on the pretreatment of rats with various monooxygenase inducers. Carcinogenesis 4:905-910. 70 245. Jacobson, J.L., G.G. Fein, S.W. Jacobson, P.M. Schwartz, and J.K. Dowler. 1984a. The transfer of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) across the human placenta and into maternal milk. Am. J. Public Health 74:378-379. 246. Jacobson, J.L., H.E.B. Humphrey, S.W. Jacobson, S.L. Schantz, M.D. Mullin, and R. Welch. 1989. Determinants of polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), and dichlorodiphenyl trichlorethane (DOT) levels in the sera of young children. Am. J. Public Health 79:1401-1404. 247. Jacobson, J.L. and S.W. Jacobson. 1988. New methodologies for assessing the effects of prenatal toxic exposure on cognitive functioning in humans. In Toxic Contaminants and Ecosystem Health: A Great Lakes Focus. M. Evans, editor. John Wiley and Sons, New York. 248. Jacobson, J.L., S.W. Jacobson, G.G. Fein, P.M. Schwartz, and J.K. Dowler. 1984b. Prenatal exposure to an environmental toxin: a test of the multiple effects model. Dev. Psychol. 20:523-532. 249. Jacobson, J J-., S.W. Jacobson, and H.E.B. Humphrey. 1990a. Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J. Pediatr. 116:38-45. 250. Jacobson, J.L., S.W. Jacobson, and H.E.B. Humphrey. 1990b. Effects of exposure to PCBs and related compounds on growth and activity in children. Neurotoxicol. Teratol. 12:319-326. 251. Jacobson, S.W., G.G. Fein, J.L. Jacobson, PJvI. Schwartz, and J.K. Dowler. 1985. The effect of PCB exposure on visual recognition memory. Child Dev. 56:853-860. 252. James, M.O. and P J. Little. 1981. Polyhalogenated biphenyls and phenobarbital: evaluation as inducers of drug metabolizing enzymes in the sheepsbead,Afchosargus probatocephahis. Chem. -BioL Interact. 36:229- 248. 253. Jan, J., M. Tratnik, and A. Kenda. 1988. Atmospheric contamination with polychlorinated biphenyls in Bela Krajina (Yugoslavia): emissions from industrial plant, landfill, and river areas. Chemosphere 17:809-813. 254. Jannetti, R A. and L.M. Anderson. 1981. Dimethylnitrosamine demethylase activity in fetal, suckling, and maternal mouse liver and its transplacental and transmammary induction by polychlorinated biphenyls. /. Natl. Cancer Inst. 67:461-466. 255. Janz, D.M. and C.D. Metcalfe. 1991. Nonadditive interactions of mixtures of 2,3,7,8-TCDD and 3,3',4, 4'-tetrachlorobiphenyl on aryl hydrocarbon hydroxylase induction in rainbow trout (Oncorhynchus my kiss). Chemosphere 23:467-472. 250. Jefferies, D J. and J.L.F. Parslow. 1976. Thyroid changes in PCB-dosed guillemots and their indication of one of the mechanisms of action of these materials. Environ. Pollution 10:293-311. 257. Jenke, H-S. 1985. Polychlorinated biphenyls interfere with the regulation of hydroxymethylglutaryl-coenzyme A reductase activity in rat liver via enzyme-lipid interaction and at the transcriptional level. Biochim. Biophys. Acta 837:85-93. 258. Jenke, H-S., M. Lowel, and J. Berndt. 1988. Modes of action and combination effects of gamma- hexachlorocyclohexane on the regulation of rat liver 3-hydroxy-3-methylglutaryl coenzymeA reductase. Chem. BioL Interact. 65:175-186. 259. Jenke, H-S., G. Michel, S. Hornhardt, and J. Berndt 1991. Protooncogene expression b rat liver by polychlorinated biphenyls (PCB). Xenobiotica 21:945-960. 71 260. Jensen, AA. 1989. Background levels in humans. In Halogenated Biphenyis, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. R.D. Kimbrough and AA. Jensen, editors. Elsevier Science Publishers, 345. 261. Jensen, R.K., S.D. Sleight, S.D. Aust, J.I. Goodman, and J.E. Trosko. 1983. Hepalic tumor-promoting ability of 3,3>,4,4',5,5'-hexabromobiphenyl: the interrelationship between toxicity, induction of hepatic microsomal drug metabolizing enzymes, and tumor-promoting ability. Toxicol. Appi Pharmacol. 71:163-176. 262. Jensen, S. and B. Jansson. 1976. Antropogenic substances in seal from the Baltic: methylsulphone metabolites of PCB and DDE. Ambio 5:257-260. 263. Jensen, S. and G. Sundstrom. 1974. Structures and levels of most chlorobiphenyls in the technical PCB products and in human adipose tissue. Ambio 3:70-76. 264. Johansscn, B. 1987. Lack of effects of polychlorinated biphenyis on testosterone synthesis in mice. PhaimacoL Toxicol. 61:220-223. 265. Jonsson, H.T.Jr., Walkerjr., W.B. Greene, M.D. Hughson, and G.R. Hennigar. 1981. Effects of prolonged exposure to dietary DDT and PCB on rat liver morphology. Arch. Environ. Contam. Toxicol, 10:171-183. 266. Kamataki, T., M. Ando, K. Ishii, and R. Kato. 1980. Inhibition by SKF 525-A of 7-ethoxycoumarin O- deethylation in microsomal and the reconstituted monooxygenase systems from PCB-treated rat livers. Japan. J. Pharmacol. 30:841-851. 267. Kamohara, K., N. Yagi, and Y. Itokawa. 1984. Mechanism of lipid peroxide formation in polychlorinated biphenyis (PCB) and dichlorodiphenyltrichloroethane (DDT)-poisoned rats. Environ. Res. 34:18-23. 268. Kannan, N., S. Tanabe, M. Ono, and R. Tatsukawa. 1989. Critical evaluation of polychlorinated biphenyl toxicity in terrestrial and marine mammals: increasing impact of non-ortho and moao-ortho coplanar polychlorinated biphenyis from land to ocean. Arch. Environ. Contam. Toxicol. 18:850-857. 269. Kannan, N., S. Tanabe, and R. Tatsukawa. 1988a. Potentially hazardous residues of non-ortho chlorine substituted coplanar PCBs in human adipose tissue. Arch. Environ. Health 43:11-14. 270. Kannan, N., S. Tanabe, and R. Tatsukawa. 1988b. Toxic potential of aoa-ortho and moao-onho coplanar PCBs in commercial PCB preparations: 23,7,8-T4CDD toxicity equivalence factors approach. Bull. Environ. Contam. Toxicol. 41:267-276. 271. Kannan, N., S. Tanabe, T. Wakimoto, and R. Tatsukawa. 1987. Coplanar polychlorinated biphenyis in Aroclor and Kanechlor mixtures. /. Assoc. Off. Anal. Chem. 70:451. 272. Kashimoto, T., H. Miyata, S. Kunita, T.C. Tung, S.T. Hsu, KJ. Chang, S.Y. Tang, G. Ohi, J. Nakagawa, and S.I. Yamamoto. 1981. Role of polychlorinated dibenzofuran in Yusho (PCB poisoning). Arch. Environ. Health 32:321-326. 273. Kasza, L., W.T. Collins, C.C. Capen, L.H. Garthoff, and L. Friedman. 1978a. Comparative toxicity of polychlorinated biphenyis and polybrominated biphenyl in the rat thyroid gland: light and electron microscopic alterations after subacute dietary exposure. /. Environ. Pathol. Toxicol. 1:587-599. 274. Kasza, L., MA. Weinberger, D.E. Hinton, B.F. Trump, C. Patel, L. Friedman and L.H. Garthoff. 1978b. Comparative toxicity of polychlorinated biphenyis and polybrominated biphenyl in the rat liver: light and electron microscopic alterations after subacute dietary exposure./. Environ. Pathol. Toxicol. 1:241-257. 72 275. Kawanishi, S., Y. Seki, and S. Sano. 1981. Polychlorobiphenyls that induce a-aminolevulinic acid synthetase inhibit uroporphyrinogen decarboxylase in cultured chick embryo liver cells. FEES Letters 129:93-%. 276. Kawanishi, S., Y. Seki, and S. Sano. 1983. Uroporphyrinogen decarboxylase: purification, properties, and inhibition by polychlorinated biphenyl isomers. J. Biol. Chem. 258:4285-4292. 277. Kerkvliet, N.I. and L. Baecher-Steppan. 1988. Suppression of allograft immunity by 3.4.5,3',4',5'- hexachlorobiphenyl. II. Effects of exposure on mixed lymphocyte reactivity and induction of suppressor cell activity in vitro. Immunopharmacology 16:13-23. 278. Kerkvliet, N.I. and L. Baecher-Steppan. 1988. Suppression of allograft immunity by 3,4,5,3',4',5'- hexachlorobiphenyl. I. Effects of exposure on tumor rejection and cytotoxic T cell activity in vivo. Immunopharmacology 16:1-12. 279. Kerkvliet, N.I. and D J. Kimeldorf. 1977. Antitumor activity of a polychlorinated biphenyl mixture, Aroclor 1254, in rats inoculated with Walker 256 carcinosarcoma cells. /. Natl. Cancer Inst. 59:951-955. 280. Kihlstrbm, I.E., M. Olsson, S. Jensen, A. Johansson, J. Ahlbom, and A. Bergman. 1992. Effects of PCB and different fractions of PCB on the reproduction of the mink (Mustela vison). Ambio 21:563-569. 281. Kilburn, K.H., R.H. Warsaw, and M.G. Shields. 1989. NeurobehavioraJ dysfunction in firemen exposed to polychlorinted biphenyls (PCBs): possible improvement after detoxification. Arch. Environ. Health 44:345-350. 282. Kimbrough, R.D. 1985. Laboratory and human studies on polychlorinated biphenyls (PCBs) and related compounds. Environ. Health Perspect. 59:99-106. 283. Kimbrough, R., J. Buckley, L. Fishbein, G. Flamm, L. Kasza, W. Marcus, S. Shibko and R. Teske. 1978. Animal toxicology. Environ. Health Perspect. 24:173-184. 284. Kimbrough, R.D. and P. Grandjean. 1989. Occupational exposure. In Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. R.D. Kimbrough and A A. Jensen, editors. Elsevier Science Publishers, Amsterdam. 485-507. 285. Kimbrough, R.D., R.E. Linder, and T.B. Gaines. 1972. Morphological changes in livers of rats fed polychlorinated biphenyls. Arch. Environ. Health 25:354-364. 286. Kimbrough, R.D., RA. Squire, R.E. Under, J.L. Strandberg, R J. Montali, and V.W. Burse. 1975. Induction of liver tumors in Sherman strain female rats by PCB Aroclor 1260. /. Natl. Cancer Inst. 55:1453-1459. 287. Kimura, N.T., T. Kanematsu, and T. Baba. 1976. Polychlorinated biphenyl(s) as a promoter in experimental hepatocarcinogenesis in rats. Z. Krebsforsch. 87:257-266. 288. Kimura, N.T. and T. Baba. 1973. Neoplastic changes in the rat liver induced by polychlorinated biphenyls. Gann. 64:105-108. 289. Kiyohara, C, T. Hirohata, and N. Mohri. 1990a. Effects of 3-methylsulphonyl-4,5,3',4'-tetrachlorobiphenyl and 3,8-benzoQavone on mouse liver aryl hydrocarbon hydroxylase activity in vitro. Toxic, in Vitro 4:103-107. 290. Kiyohara, C., N. Mohri, T. Hirohata, K. Haraguchi, and Y. Masuda. 1990b. In vitro effects of methylsulfonyl polychlorinated biphenyls and 3,8-benzoflavone on aryl hydrocarbon hydroxylase activity in human lymphoblastoid cells. Pharmacol. Toadcol. 66:273-276. 73 291. Kiyohara, C., M. Omura, T. Hirohata, and Y. Masuda. 1992. Comparison of suppression of mutagcnicity ofbenzo(a)pyreneamongmethylsulfonylpolychlorinatedbiphenylisomers.Bu//.Environ.Contam. Toxicol. 48:877-883. 292. Klasson Wehler, E., H. Kuroki, M. Alhanasiadou, and A. Bergman. 1992. Selective retention of hydroxylated PCBs in blood. Organohalogen Compounds, Dicadn '92 10:121-122. Abstract. 293. Klasson-Wehler, E., B. Brunstrom, U. Rannug, and A. Bergman. 1990. 3,3',4,4'-Tetrachlorobiphenyl: metabolism by the chick embryo in ovo and toxicity of hydroxylated metabolites. Chem. -Bioi. Interact. 73:121-132. 294. Kling, D. and W. Gamble. 1991. In vivo inhibition of citrate cleavage enzyme by polychlorinated biphenyls. Expfrientia 37:1258-1259. 295. Kling, D., J. Kunkle, A.S. Roller, and W. Gamble. 1978. Polychlorinated biphenyls: in vivo and in vitro modifications of cholesterol and fatty acid biosynthesis. /. Environ. Palhol. Toxicol. 1:813-828. 296. Kodba, RJ., D.G. Keyes, J.E. Beger, R.M. Caireon, C.E. Wade, DA. Dittenber, R.P. Kalnins, L.E. Frauson, C.L. Park, S.D. Barnard, RA. Hummel, and C.G. Humiston. 1978. Results of a 2-year chronic toxicity and oncogenicity of 23,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. TaxicoL Appl. PharmacoL 46:279-303. 297. Koga, N., M. Beppu, and H. Yoshimura. 1990. Metabolism in vivo of 3,4,5,3',4'-pentachlorobiphenyl and lexicological assessment of the metabolite in rats. /. Pharmacobio-Dyn. 13:497-506. 298. Kohli, K.K., B.N. Gupta, P.W. Albro, and J.D. McKinney. 1981a. Effects of inducers of drug metabolism enzymes on triglyceride and phospholipid biosynthesis. Chem. -Biol. Interact. 36:117-121. 299. Kohli, K.K., B.N. Gupta, P.W. Albro, H. Mukhtar, and J.D. McKinney. 1979a. Biochemical effects of pure isomers of hexachlorobiphenyl: fatty livers and cell structure. Chem. -Biol. Interact. 25:139-156. 300. Kohli, K.K., P. Linko, and JA. Goldstein. 1981b. Multiple forms of solubilized and partially resolved cytochrome P-450 from rats induced by 23,5,2',3',5'-and 3,4,53',4',5'-hexachlorobiphenyls. Biochem. Biophys. Res. Comm. 100:483-490. 301. Kohli, K.K., H. Mukhtar, J.R. Bend, P.W. Albro, and J.D. McKinney. 1979b. Biochemical effects of pure isomers of hexachlorobiphenyl -hepatic microsomal epoxide hydrase and cytosolic glutathione 5-transferase activities in the rat. Biochem. Phamacol. 28:1444-1446. 302. Kohli, KJC. R.M. Philpot, P.W. Albro, and J.D. McKinney. 1980. Induction of different species of cyiochrome P-450 by coplanar and non-coplanar isomers of hexachlorobiphenyl. Life Sci. 26:945-952. 303. Koller, L.D. 1977. Enhanced polychlorinated biphenyls lesions in Moloney leukemia virus-infected mice. Clin. Toxicol. 11:107-116. 304. KoUer, L.D. and J.G. ZinkL 1973. Pathology of polychlorinated biphenyls in rabbits.>lm. /. PathoL 70:363-377. 305. Korach, K.S., P. Sarver, K. Chae, JA. Mclachlan, and J.D. McKinney. 1988. Estrogen receptor-binding activity of polychlorinated hydroxybiphenyls: conformationally restricted structural probes. Mol. Phamacol 33:120-126. 306. Koval, PJ., TJ. Peterle, and J.D. Harder. 1987. Effects of polychlorinated biphenyls on mourning dove reproduction and circulating progesterone levels. Bull. Environ. Contam. Toxicol. 39:663-670. 74 307. Krauss. P.P., K. Suns, and E.H. Buckley. 1983. Monitoring of PCBs in water, sediments and biota of the Great Lakes - some recent examples. In Physical Behavior of PCBs in the Great Lakes. D. Mackay, S. Paterson, SJ. Eisenreich, and M.S. Simmons, editors. Ann Arbor Science, Ann Arbor, MI. 385-409. 308. Kreiss, K. 1985. Studies on populations exposed to polychlorinatcd biphenyls. Environ. Health Perspect. 60:193-199. 309. Krishnan, V. and S. Safe. 1993. Polychlorinated biphenyls (PCBs), dibenzo-/?,dioxins (PCDDs) and dibenzofurans (PCDFs) as antiestrogens in MCF-7 human breast cancer cells: quantitative structure-activity relationships. Toxicol. Appl. Pharmacol. In press. 310. Kunita, N., T. Kashimoto, H. Miyata, S. Fukushima, S. Hori, and H. Obana. 1984. Causal agents of Yusho. Amer. J. Ind. Med. 5:45-58. 311 Kuratsune, M. 1980. Yusho. In Halogenated Biphenyls, Terphenyts, Naphthalenes, Dibenzodioxins and Related Products. R.D. Kimbrough, editor. Elsevier/North Holland Biomedical Press, Amsterdam. 287-302. 312. Kuratsune, M. 1989. Yusho, with reference to Yu-Cheng. In Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. R.D. Kimbrough and AA. Jensen, editors. Elsevier. Amsterdam. 381-400. 313. Kuratsune, M. and R.E. Shapiro. 1984. PCB Poisoning in Japan and Taiwan. Alan R. Liss, New York. 314. Kuroki, H. and Y. Masuda. 1977. Structures and concentrations of the main components of polychlorinated biphenyls retained in patients with Yusho. Chemosphere 6:469-474. 315. Kutz, F.W., D.G. Barnes, E.W. Bretthauer, D.P. Bottimore, and H. Greim. 1990. The international toxicity equivalency factor (I-TEF) method for estimating risks associated with exposures to complex mixtures of dioxins and related compounds. Toxicol. Environ. Chem. 26:99-109. 316. Laib, R.M., N. Rose, and H. Bunn. 1991. Hepatocarcinogenicity of PCB congeners. Toxicol. Environ. Chem. 34:19-22. 317. Lake, E.G., MA. Collins, R A. Harris, and S.D. Gangolli. 1979. The induction of hepatic and extrahepatic xenobiotic metabolism in the rat and ferret by a polychlorinated biphenyl mixture (Aroclor 1254). Xenobiotica 9:723-731. 318. Lambrecht, R.W., J.M. Jacobs, P.R. Sinclair, and J.F. Sinclair. 1990. Inhibition of uroporphyrinogen decarboxylase activity. The role of cytochrome P-450-mediated uroporphyrinogen oxidation. Biochem. J. 269:437-441. 319. Larsen, G.L., J.K. Huwe, A. Bergman, E. Klasson-Wehler, and P. Hargis. 1992. Methylsulfonyl metabolites of xenobiotics can serve as ligands for fatty acid binding proteins in chicken liver and intestinal mucosa. Chemosphere 25:1189-1194. 320. Lawton, R.W., M.R. Ross, J. Feingold, and J.F. Brown. 1985. Effects of PCB exposure on biochemical and hematological findings in capacitor workers. Environ. Health Perspect. 60:165-184. 321. Leece, B., MA. Denomme, R. Towner, and S.MA. LI 1985. Polychlorinated biphenyls: correlation between in vivo and in vitro quantitative structure-activity relationships (QSARs)./. Toxicol. Environ. Health 16:379-388. 322. Leece, B., MA. Denomme, R. Towner, A. Li, J.P. Landers, and S. Safe. 1987. Nonadditive interactive 75 effects of polychlorinated biphcnyi congeners in rats: role of the 2^3,7,8-tetrachlorodibenzo-p-dioxin receptor. Can. J. Physiol. Pharmacol. 65:1908-1912. 323. Levin, E.D., S.L. Schantz, and R.E. Bowman. 1988. Delayed spatial alternation deficits resulting from perinatal PCB exposure in monkeys. Arch. Toxicol. 62:267-273. 324. Lewin, C., WA. McBlain. and F.H. Wolfe. 1972. Acute intraperitoneal toxicity of DOT and PCBs in mice using two solvents. Bull. Environ. Contam. Toxicol. 8:245-250. 325. Lilienthal, H., M. Neuf, C. Munoz, and G. Winneke. 1990. Behavioral effects of pre- and postnatal exposure to a mixture of low chlorinated PCBs in rats. Fund. Appl. Toxicol. 15:457-467. 326. Lilienthal, H. and G. Winneke. 1991. Sensitive periods for behavioral toxicity of poiychlorinated biphenyls: determination by cross-fostering in rats. Fund. Appl. Toxicol. 17:368-375. 327. Lillie, R J., H.C. Cecil, J. Bitman, and G.F. Fries. 1974. Differences in response of caged white leghorn layers to various polychlorinated biphenyls (PCBs) in the diet. Poultry Science 53:726-732. 328. Linder, R.E., T.B. Gaines, and R.D. Kimbrough. 1974. The effect of polychlorinated biphenyls on rat reproduction. Food Cosmet. Toxicol. 12:63-77. 329. Linzey, A.V. 1988. Effects of chronic polychlorinated biphenyls exposure on growth and reproduction of second generation white-footed mice (Peromyscusleucopus). Arch. Environ. Contam. Toxicol. 17:39-45. 330. Loo, J .C.K., H. Tryphonas, N. Jordan, R. Brien, K.F. Karpinski, and D.L. Arnold. 1989. Effects of Aroclor 1254 on hydrocortisone levels in adult rhesus monkeys (Macaco mulatto). Bull. Environ. Contam. Toxicol. 43:667-669. 331. Loose, L.D., ICA. Pittman, K-F. Benitz, J.B. Silkworth, W. Mueller, and F. Coulston. 1978a. Environmental chemical-induced immune dysfunction. Ecotoxicol. Environ. Safety 2:173-198. 332. Loose, L.D., J.B. Silkworth, 1CA. Pittman, K-F. Benitz, and W. Mueller. 1978b. Imparied host resistance to endotoxin and malaria in polychlorinated biphenyl- and hexachlorobenzene-treated mice. Inf. Immun. 20:30-35. 333. Lubet, R.A., B.N. Lemaire, D. Avery, and R.E. Kouri. 1986. Induction of immunotoxicity in mice by polyhalogenated biphenyls. Arch. Toxicol. 59:71-77. 334. Lubet, R.A., R.W. Nims, L.E. Beebe, S.D. Fox, HJ. Issaq, and K. Mcbee. 1992. Induction of hepatic CYPIA activity as a biomarker for environmental exposure to Aroclor-1254 in feral rodents./lrc/i. Environ. Contam. Toxicol. 22:339-344. 335. Lubet, R.A., C.R. Jones, D.L. Stockus, S.D. Fox, and R.W. Nims. 1991. Induction of cytochrome P450 and other drug metabolizing enzymes in rat liver following dietary exposure to Aroclor 1254. Toxicol. Appl. Pharmacol. 108:355-365. 336. Luebeck, E.G., S.H. Moolgavkar, A. Buchmann, and M. Schwarz. 1991. Effects of polychlorinated biphenyls in rat liver: quantitative analysis of enzyme-altered foci. Toxicol. Appl. Pharmacol. 111:469-484. 337. Lund, B.O, A. Bergman, and I. Brandt. 1986a. Decreased pulmonary drug metabolism in mice treated with the PCB metabolite 4-methylsulphonyl-2,2',5)5'-tetrachlorobiphenyl. Toxicol. Lett. 32:261-267. 338. Lund, J., O. Andersson, and E. Ripe. 1986b. Characterization of a binding protein for the PCB metabolite 76 4, 4'-6ts(methylsulfonyl)-Z,2'r5,5'-tetrachlorobiphenyl present in bronchoalveolar lavage from healthy smokers and non-smokers. Toxicol. Appl. Pharmacol. 83:486-493. 339. Lund, J., I. Brandt, L. Poellinger, A. Bergman, E. Klasson-Wehler, and J-A. Gustafsson. 1985. Target cells for the polychlorinated biphenyl metabolite 4,4'-bis(methylsulfonyl)-2,2',5,5'-tetrachlorobiphenyl: charcterization of high affinity binding in rat and mouse lung cytosol. Mol. Phamacol. 27:314-323. 340. Lundkvist, U. 1990. Clinical and reproductive effects of Clophen A50(PCB) administered during gestation on pregnant guinea pigs and their offspring. Toxicology 61:249-257. 341. Luster, M.I., L.D. Lawson, P. Linko, and JA. Goldstein. 1983. Immunochemical evidence for two 3- methylcholanthrene-inducible forms of cytochrome P-448 in rat liver microsomes using a double-antibody radioimmunoassay procedure. Mol. Pharmacol. 23:252-257. 342. Made], A., M. Forsberg, and L-E. Edqvist. 1992. Urinary excretion of cortisol and oestrone sulfate in pregnant mink fed PCS and fractions of PCB. Ambio 21:582-585. 343. Manis, J. and G. Kim. 1980. Effects of potyhalogenated aromatic hydrocarbons on benzo(a)pyrene hydroxylase activity in the intestine and liver. Life Sciences 26:1431-1439. 344. Marks, TA., G.L. Kimmel, and R.E. Staples. 1981. Influence of symmetrical polychlorinated biphenyl isomers on embryo and fetal development in mice. I. Teratogenicity of 3,3' A 4',5,5'-hexachlorobiphenyl. Toxicol. Appl. Pharmacol. 61:269-276. 345. Marks, TA., G.L. Kimmel, and R.E. Staples. 1989. Influence of symmetrical polychlorinated biphenyl isomers on embryo and fetal development in mice. II. Comparison of 4,4'-dichlorobiphenyl, 3,3',4,4'- tetrachlorobiphenyl, 3,3',5,5'-tetrachlorobiphenyl, and 3,3',4,4'-tetramethylbiphenyl. Fund. Appl. Toxicol. 13:681-693. 346. Maroni, M., A. Columbi, G. Arbosti, S. Cantoni, and V. Foa. 1981. Occupational exposure to polychlorinated biphenyls in electrical workers. II. Health effects. Brit J. Ind. Med. 38:55-60. 347. Mayura, C., C.B. Spainhour, L. Howie, S. Safe, and T.D. Phillips. 1993. Teratogenicity and immunotoxicity of 3,3',4,4',5-pentachlorobiphenyl in C57BL/6 mice. Toxicology In press. 348. McArthur, M.L.B., G A. Fox, D.B. Peakall, and B J.R. Philogene. 1983. Ecological significance of behavioral and hormonal abnormalities in breeding ring doves fed an organochlorine chemical mixturc.Arch. Environ. Contain. Toxicol. 12:343-353. 349 McFarland, VA. and J.U. Clarke. 1989. Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis. Environ. Health Perspect 81:225-239. 350. McKinney, J.D., K. Chae, B.N. Gupta, J A. Moore, and JA. Goldstein. 1976. Toxicological assessment of hexachlorobiphenyl isomers and 2,3,7,8-tetrachlorodibenzofuran in chicks. I. Relationship of chemical parameters. Toxicol. Appl. Pharmacol. 36:65-80. 351. McNulty, W.P., G.M. Becker, and H.T. Gory. 1980. Chronic toxicity of 3,4,3',4'- and 2,5,2',5'- tetrachlorobiphenyls in rhesus macaques. Toxicol. Appl. Pharmacol. 56:182-190. 352. Melancon, M J., C.R. Elcombe, M J. Vodicnik, and J J. Lech. 1981. Induction of cytochromes P450 and mixed-function oxidase activity by polychlorinted biphenyls and /3-naphthoflavone in carp (Cyprinus carpio). Comp. Biochem. Physiol. 69:219-226. 77 353. Mes, J. and D. Weber. 1989. Non-ort/io-chlorine substituted coplanar polychlorinated biphenyl congeners in Canadian adipose tissue, breast milk and fatty foods. Chemosphere 19:1357-1365. 354. Meserve, L.A., B.A. Murray, and J A. Landis. 1992. Influence of maternal ingestion of Aroclor-1254 (PCB) or Firemaster BP-6 (PBB) on unstimulated and stimulated corticosterone levels in young rats. Bull. Environ. Contain. Toxicol. 48:715-720. 355. Miniats, O.P., N.S. Platonow, and H.D. Geissinger. 1978. Experimental polychlorinated biphenyl toxicosis in germfree pigs. Can. J. Comp. Med. 42:192-199. 356. Mio, T., K. Sumino, and T. Mizutani. 1976. Sulfur-containing metabolites of 2,2',5,5'-tetrachlorobiphenyl, a major component of commercial PCBs. Chem. Pharm. Bull. 24:1958-1960. 357. Miranda, C.L., M.C. Henderson, J-L. Wang, H.S. Nakaue, and D.R. Buhler. 1987. Effects of polychlorinated biphenyls on porphyrin synthesis and cytochrome P-450-dependent monooxygenases in small intestine ami liver of Japanese quail. /. Toxicol. Environ. Health 20:27-35. 358. Miranda, C.L., M.C. Henderson, J-L. Wang, H.S. Nakaue, and D.R. Buhler. 1992. Comparative effects of the polychlorinated biphenyl mixture, Aroclor 1242, on porphyrin and xenobiotic metabolism in kidney of Japanese quail and rat. Comp. Biochem. Physiol. 103:149-152. 359. Miranda, C.L., J-L. Wang, H-S. Chang, and D.R. Buhler. 1990. Multiple effects of 3,4,5,3',4',5'- hexachlorobiphenyl administration on hepatic cytochrome P450 isozymes and associated mixed-function oxidase activities in rainbow trout. Biochem. Pharmacol. 39:388-390. 360. Miyata, H., S. Fukushima, T. Kashimoto, and N. Kunita. 1985. PCBs, PCQs and PCDFs in the tissues of Yusho and Yu-Cheng patients. Environ. Health Perspect. 59:67-72. 361. Miyata, H. and T. Kashimoto. 1976a. The finding of polychlorodibenzofurans in commercial PCBs (Aroclor, Phenoclor and Clophen) (in Japanese). /. Food Hyg. Soc. Japan 17:434-437. 362. Miyata, H., T. Kashimoto, and N. Kunita. 1977. Detection and determination of polychlorodibenzofurans in normal human tissues and Kanemi rice oils caused "Kanemi Yusho" (in Japanese). /. Food Hyg. Soc. Japan 19:260-265. 363. Miyata, H., A. Nakamura, and T. Kahimoto. 1976b. Separation of polychlorodibenzofurans (PCDFs) in Japanese commercial PCBs (Kanechlors) and their heated preparation. /. Food Hyg. Soc. Japan 17:227-230. 364. Monossun, E. and J J. Stegeman. 1991. Cytochrome P450E (P4501A) induction and inhibition in winter flounder by 33',4,4'-tetrachlorobiphenyt: comparison of response in fish from Georges Bank and Narragansett Bay. Environ. Toxicol. Chem. 10:765-774. 365. Morales, N.M. and H.B. Matthews. 1979. In vivo binding of 2,3,6,2',3',6'-hexachlorobiphenyl and 2,4,5, 2',4>,5'-hexachlorobiphenyl to mouse liver macromolecules. Chem. -Biol. Interact. 27:94-110. 366. Morgan, R.W., J.M. Ward, and P.E. Hartman. 1981. Aroclor 1254-induced intestinal metaplasia and adenocarcinoma in the glandular stomach of F344 rats. Cancer Res. 41:5052-5059. 367. Morita, M., J. Nakagawa, K. Akiyama, S. Mimura, and N. Isono. 1977. Detailed examination of polychlorinated 'libenzofurans in PCB preparations and Kanemi Yusho oil. Bull. Environ. Contam. Toxicol. 18:67. 368. Morrissey, R.E., M.W. Harris, J J.Diliberto, and L.S. Birnbaum. 1992. Limited PCB antagonism of TCDD- 78 induced malformations in mice. Toxicol. Lett. 60:19-25. 369. Mullin, M., G. Sawka, L. Safe, S. McCrindle, and S. Safe. 1981a. Synthesis of octa- and nonachJorobiphenyl isomers and congeners and their quantitation in commercial polychlorinated biphcnyls and identification in human breast milk./. Anal. Toxicol. 5:138-142. 370. Mullin, M.D. and J.C. Filkins. 1981b. Analysis of polychlorinated biphenyls by glass capillary and packed column gas chromatography. ID Advances in the Identification and Analysis of Organic Pollutants in Water. L.W. Keith, editor. Ann Arbor Science, Ann Arbor, MI. 187-196. 371. Mullin, M.D., C.M. Pochini, S. McCrindle, M. Romkes, S. Safe, and L. Safe. 1984. High-resolution PCB analysis: the synthesis and chromatographic properties of all 209 PCB congeners. Environ. Sci. Technol. 18:468-476. 372. Murphy, TJ., J.C. Pokojowczyk, and M.D. Mullin. 1983. Vapor exchange of PCBs with Lake Michigan: the atmosphere as a sink for PCBs. In Physical Behavior of PCBs in the Great Lakes. D. Mackay, S. Paterson, SJ. Eisenreich, and M.S. Simmons, editors. Ann Arbor Science, Ann Arbor, MI. 49-58. 373. Muller, W.F., W. Hobson, G.B. Fuller, W. Knauf, F. Coulston, and F. Korte. 1978. Endocrine effects of chlorinated hydrocarbons in rhesus monkeys. Ecotcadcol. Environ. Safety 2:161-172. 374. Nagaoka, S., H. Miyazaki, Y. Aoyama, and A. Yoshida. 1990. Effects of dietary polychlorinated biphenyls on cholesterol catabolism in rats. Brit. J. Nutrition 64:161-169. 375. Nagata, K., T. Matsunaga, P. Buppodom, M. Ishmatsu, H. Yamato, S. Yoshihara, and H. Yoshimura. 1985. Unique induction of cytochrome P-450 isozymes in rat liver microsomes by treatment with 3,4,5,3',4'- pentachlorobiphenyl and its effect on testosterone metabolism. /. Pharmacobio-Dyn. 8:948-957. 376. Narasimhan, T.R., H.L. Kim, and S. Safe. 1991. Effects of hydroxylated polychlorinated biphenyls on mouse liver mitochondria! oxidative phosphorylation. /. Biochem. Toxicol. 6:229-236. 377. Narbonne, J-F., P. Grolier, R. Albrecht, V. Azais, F. Oesch, and L.W. Robertson. 1990. A time course investigation of vitamin A level and lipid conposition of the liver endoplasmic reticulum in rats following treatment with congeneric polychlorobiphenyis. Toxicology 60:253-261. 378. Narbonne, J.F. 1978. Effect of age and sex on liver response to Phenoclor DP6, a polychlorinated biphenyl, in the rat. Bull. Environ. Contam. Toxicol. 20:662-667. 379. Narbonne, J.F. 1979a. Effects of age and sex on liver responses of Phenoclor DP6, a polychlorinated biphenyl in the rat. Bull. Environ. Contam. Toxicol. 22:49-54. 380. Narbonne, J.F. 1979b. In vitro effects of phenoclor DP6 on drug metabolism in rat liver. Bull. Environ. Contam. Toxicol. 23:344-348. 381. Narbonne, J.F. 1980. Time course of induction of microsomal enzymes following dietary administration of a polychlorinated biphenyl (Phenoclor DP6). Toxicol. Appl. Pharmacol. 56:1-7. 382. Narbonne, J.F., P. Suteau, M. Daubeze, and C. Audy. 1987. Polycyclic aromatic hydrocarbon metabolism in mullets, Chelonlabrosus, treated by polychlorinated biphenyls. Bull. Environ. Contam. Toxicol. 38:53-57. 383. Nath, R.G, E. Randerath, and K. Randerath. 1991. Short-term effects of the tumor promoting polychlorinated biphenyl mixture, Aroclor 1254, on I-compounds in liver, kidney and lung DNA of male Sprague-Dawley rats. Toxicology 68:275-289. 79 384. NATO/CCMS, 1988. North Atlantic Treaty (NATO)/Committee on the Challenges of Modern Society (CCMS), Report Number 176. 385. NCI (National Cancer Institute), 1978. Bioassay of Aroclor 1254 for possible carcinogenicity. CAS No. 27323-18-8. NCI Carcinogenesis Tech. Rep. Ser. No. 38 386. Nelson. N.N, P.B. Hammon, I.C.T. Nisbet, A.F. Sarofim, and W.H. Drury. 1972. Polyclorinaled biphenyls - environmental impact. Environ. Res. 5:249-362. 387. Nikolaidis, E., B. Brunstrom, and L. Dencker. 1988a. Effects of the TCDD congeners 3,3',4,4'- tetrachlorobiphenyi and 33',4,4'-tetrachloroazoxybenzene on lymphoid development in the bursa of fabritius of the chick embryo. Toxicol. Appl. Pharmacol. 92:315-323. 388. Nikolaidis, E., B. Brunstrom, and L. Dencker. 1988b. Effects of TCDD and its congeners 3,3',4,4'- tetrachloroazoxybenzene and 3,3',4,4'-tetrachlorobiphenyl on lymphoid development in the thym us of avian embryos. Pharmacol. Toxicol. 63:333-336. 389. Nishihara, Y. 1988. Comparative toxicity of 4-chlorobiphenyl and its metabolite 4-chloro-4'-biphenylol in isolated rat liver mitochondria. Biochem. Pharmacol. 37:2915-2926. 390. Nishihara, Y. and K. Utsumi. 1987. 4-Chloro-4'-biphenylol as an uncoupler and an inhibitor of mitochondria! oxidative phosphorylation. Biochem. Pharmacol. 36:3453-3457. 391. Nishizumi, M. 1976. Enhancement of diethylnitrosamine hepatocarcinogenesis in rats by exposure to potychlorinated biphenyls or phenobarbital. Cancer Lett. 2:11-16. Nishizumi, M. 1979. Effects of phenobarbital, dichlorodiphenyltrichlorethane and polychlorinated biphenyls on diethylnitrosamine-induced hepatocarcinogenesis. Gann 70:835-837. 392. Norback, D.H. and R.H. Weltman. 1985. Polychlorinated biphenyl induction of hepatocellular carcinoma in the Sprague-Dawley rat. Environ. Health Perspect. 60:97-105. 393. Nordqvist, M., D.R. Thakker, W. Levin, H. Yagi, D.E. Ryan, P.E. Thomas, A.H. Conney, and D.M. Jerina. 1979. The highly turnorigenic 3,4-dihydrodiol is a principal metabolite formed from dibenzo[a,h]anthracene by liver enzymes. Mol. Pharmacol. 16:643-655. 394. O'Keefe, P.W. and R.M. Smith. 1989. PCB capacitor/transformer accidents. In Halogenated Biphenyls, Terphenyls, Naphthalene, Dibenzodioxins and Related Products. R.D. Kimbiough and AA. Jensen, editors. Elsevier Science Publishers, 417-444. 395. Oesterle, D. and E. Deml. 1983. Promoting effect of polychlorinated biphenyls on development of enzyme- altered islands in livers of weanling and adult rats. /. Cancer Res. Clin. Oncol. 105:141-147. 3%. Oesterle, D. and E. Deml. 1984. Dose-dependent promoting effect of polychlorinated biphenyls on enzyme- altered islands in livers of adult and weanling rats. Carcinogenesis 5:351-355. 397. Orberg, J. and J.E. Kihlstrom. 1973. Effects of long-term feeding of polychlorinated biphenyls (PCB, Clophen A60) on the length of the oestrous cycle and on the frequency of implanted ova in the mouse. Environ. Res. 66:176-179. 398. Ouw, H.K., G.R. Simpson, and D.S. Siyali. 1976. Use and health effects of Aroclor 1242, a polychlorinated biphenyl in an electrical industry. Arch. Environ. Health 31:189-194. 80 399. Overmann, S.R., J. Kostas, L.R. Wilson, W. Shain, and B. Bush. 1987. Neurobehavioral and somatic effects of perinatal PCB exposure in rats. Environ. Res. 44:56-70. 400. Ozawa, N., S. Yoshihara, K. Kawano, Y. Okada, and H. Yoshimura. 1979a. 3,4,5,3',5'-PentachlorobiphenyI as a useful inducer for purification of rat liver microsomaJ cytochrome P448. Biochem. Biophys. Res. Comm. 91:1140-1147. 401. Ozawa, N., S. Yoshihara, and H. Yoshimura. 1979b. Selective induction of rat liver microsomal cytochrome P-448 by 3,4,5,3',5'-pentachlorobiphenyl and its effect on liver microsomal drug 'metabolism./. Pharm. Dyn. 2:309-319. 402. Orberg, J. and C. Lundberg. 1974. Some effects of DOT and PCB on the hormonal system in the male mouse. Environ. Physiol. Biochem. 4:116-120. 403. Paivi, K., M. Erkki, and K. Sirpa. 1992. Induction of aryl hydrocarbon hydroxylase AHH by two previously uncharacteri/ed pentachlorinated biphenyis in a mouse and a rat hepatoma cell line. Chemosphere 24:201-210. 404. Pantaleoni, G-C, D. Fanini, A.M. Sponta, G. Palumbo, R. Giorgi, and P.M. Adams. 1988. Effects of maternal exposure to polychlorobiphenyis (PCBs) on Fl generation behavior in the rat. Fund. Appl. TcadcoL 11:440-449. 405. Parkinson, A., R. Cockerline, and S. Safe. 1980a. Induction of both 2-methyicholantrene- and phenobarbitone- type microsomal enzyme activity by a single polychlorinated biphenyi isomer. Biochem. PharmacoL 29:259-262. 406. Parkinson, A^ R. Cockerline, and S. Safe. 1980b. Porychlorinated biphenyi isomers and congeners as inducers of both 3-methylcholanthrene- and phenobarbitone-type microsomal enzyme activity. Chem. -Biol. Interact. 29:277-289. 407. Parkinson, A., L. Robertson, L. Safe, and S. Safe. 1981a. Polychlorinated biphenyis as inducers of hepatic microsomal enzymes: structure-activity rules. Chem. -Biol. Interact. 30:271-285. 408. Parkinson, A., L. Robertson, L. Safe, and S. Safe. 198 Ib. Polychlorinated biphenyis as inducers of hepatic microsomal enzymes: effects of stiortho substitution. Chem. -Biol. Interact. 31:1-12. 409. Parkinson, A., L. Robertson, and S. Safe. 1980c. Hepatic microsomal enzyme induction by 2,2',3,3',4,4'- and 2,2', 3',4,4',5-hexachlorobiphenyl. Life Sci. 27:2333-2337. 410. Parkinson, A., L. Robertson, L. Uhlig, MA. Campbell, and S. Safe. 1982.2,3,4,4',5-Pentachlorobiphenyl: differential effects on C57BL/6J and DBA/2J inbred mice. Biochem. PharmacoL 31:2830-2833. 411. Parkinson, A., S. Safe, L. Robertson, P.E. Thomas, D.E. Ryan, and W. Levin. 1983. Immunochemical quantitation of cytochrome P-450 isozymes and epoxide hydrolase in liver microsomes from polychlorinated and polybromtnated biphenyis: a study of structure activity relationships. /. Biol. Chem. 258:5967-5976. 412. Parklti, M.G., J. Marniemi, and H. Vainio. 1977. Long-term effects of single and combined doses of DOT and PCB on drug-metabolizing enzymes in rat liver. /. Taricol. Environ. Health 3:903-911. 413. Paustenbach, D J., R J. Wenning, V. Lau, N.W. Harrington, O.K. Rennix, and A.H. Parsons. 1992. Recent developments on the hazards posed by 2^,7,8-tetrachlorodibenzo-p-dioxin in soil: implications for setting risk-based cleanup levels at residential and industrial sites. /. Tcodcol. Environ. Health 36:103-149. 414. Pelissier, MA., C. Frayssinet, M. Boisset, and R. AlbrechL 1992. Effect of phenoclor DP6 on enzyme-altered foci and lipid peroxidation in livers of aflatoxin Bl-initiated rats. Food Chem. Taacol. 30:133-137. 81 415. Pelissier, MA., N. Miladi, S. Alteba, J.F. Narbonne, and R. Albrecht. 1985. Polychlorobiphenyle (Phenodor DP6) et metabolisme des xenobiotiques: effets d'un regime hyperlipieique. Fd. Oiem. Toxic. 23:805-808. 416. Pellizzari, E., MA. Moseley, and S.D. Cooper. 1985. Recent advances in the analysis of polychlortnatcd biphenyls in environmental and biological media. /. Chromatogr. 334:277-314. 417. Pereira, MA., S.L. Herren, A.L. Britt, and M.M. Khoury. 1982. Promotion by polychlorinated biphenyls of enzyme-altered foci in.rat liver. Cancer Lett. 15:185-190. 418. Pilot, H.C.,T. Goldsworthy, HA. Campbell, and A. Poland. 1980. Quantitative evaluation of the promotion by 23,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethyinitrosamine. Cancer Res. 40:3616- 3620. 419. Poland, A. and E. Glover. 1977. Chlorinated biphenyl induction of aryl hydrocarbon hydroxylase activity: a study of the structure activity relationship. Mol. Pharmacol. 13:924-938. 420. Poland, A., W.F. Greenlee, and A.S. Kende. 1979. Studies on the mechanism of action of the chlorinated dibenzo-p-dioxins and related compounds. Ann. N. Y. Acad. Sci. 320:214-230. 421. Poland, A. and J.C. Knutson. 1982a. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons. Examinations of the mechanism of toxicity. Anna. Rev. Pharmacol. Toxicol. 22:517-554. 422. Poland, A., D. Palen, and E. Glover. 1982b. Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 300:271-273. 423. Powers, R.H., L.C. Gilbert, and S.D. Aust. 1987. The effect of 3,4,3',4'-tetrachlorobiphenyl on plasma retinol and hepatic retinyl palmitate hydrolase activity in female Sprague-Dawiey rats. Toxicol. Appi. Pharmacol. 89:370-377. 424. Preston, B.D., J.D. Miller, and E.G. Miller. 1984. Reactions of 2,2',5,5'-tetrachlorobiphenyI 3,4-oxide with methionine, cysteine and glutathione in relation to the formation of methylthio-metabolites of 2,2',5,5'- tetrachlorobiphenyl in the rat and mouse. Chem. -Biol. Interact. 50:289-312. 425. Preston, B.D., J.P. Van Miller, R.W. Moore, and J.R. Alien. 1981. Promoting effects of polychlorinated biphenyls (Aroclor 1254) and polychlorinated dibenzofuran-free Aroclor 1254 on diethylnitrosamine-induced tumorigenesis in the rat. /. Natl. Cancer Inst. 66:509-515. 426. Rao, C. V. and A.S. Banerji. 1988a. Induction of liver tumors in mle Wistar rats by feeding polychlorinated biphenyls (Aroclor 1260). Cancer Letters 39:59-67. 427. Rao, MS., V. Subbarao, J.D. Prasad, and D.G. Scarpelli. 1988b. Carcinogenicity of 23,7,8-tetrachlorodibenzo- /7-diorin in the Syrian golden hamster. Carcinogenesis 9:1677-1679. 428. Rickenbacher, U., J.D. McKinney, S J. Oatley, and C.C.F. Klake. 1986. Structurally specific binding of halogenated biphenyls to thyroxine transport protein. /. Med. Chem. 29:641-648. 429. Rinzky, A. and A.S. Perry. 1981. Induction of the mixed-function oxidase system in the liver of the barn owl Tyto alba by PCBs. Pesticide Biochem. Physiol. 16:72-78. 430. Rinzky, A. and A.S. Perry. 1983. Postnatal development of the mixed function oxidase system in nestling bam owls and baby chicks and induction of this system in the mature forms by Aroclor 1254. Comp. Biochem. Physiol. 75:51-55. 82 431. Risebrough, R.W., P. Rieche, S.G. Herman, D.B. Peakall, and M.N. Kirven. 1968. Polychlorinated biphenyls in the global ecosystem. Nature 220:1098-1102. 432. Riviere, J.L., E. De Lavaur, andG.Grolleau. 1978. Effect of polychlorinatedbiphenyls on drug metabolism in Japanese quail and its progeny. Toxicology 11:329-334. 433. Robertson, L.W., A. Parkinson, S. Bandiera, I. Lambert, J. Merrill and S. Safe. 1984. PCBs and PBBs - biologic and toxic effects on C57BL/6J and DBA/2J inbred mice. Toxicology 31:191-206. 434. Rodman, L.E., S.I. Shedlofsky, A. Mannschreck, M. Puttmann, A.I. Swim and L.W. Robertson. 1991. Differential potency of atropisomers of polychlorinated biphenyls on cytochrome P450 induction and uroporphyrin accumulation in the chick embryo hepatocyte culture. Biochem. Pharmacol. 41:915-922. 435. Rodman, L.E., S.I. Shedlofsky, A.T. Swim, and L.W. Robertson. 1989. Effects of polychlorinated biphenyls on cytochrome P450 induction in the chick embryo hepatocyte culture. Arch. Biochem. Biophys. 275:252-262. 436. Rogan, WJ. 1989. Yu-Cheng. In Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. R.D. Kimbrough and A_A. Jensen, editors. Elsevier Science Publishers, 401-415. 437. Rogan, WJ., B.C. Gladen, K. Hung, S. Koong, L. Shih, J.S. Taylor, Y. Wu, D. Yang, N.B. Ragan, and C. Hsu. 1988. Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241:334-336. 438. Rogan, W J., B.C. Gladen, J.D. McKinney, N. Carreras, P. Hardy, J. Thullen, J. Tingelstad, and M. Tully. 1986. Neonatal effects of transplacental exposure to PCBs and DDE. /. Pediotr. 109:335-341. 439. Rogan, WJ., B.C. Gladen, J.D. McKinney, N. Carreras, P. Hardy, J. Thullen, J. Tinglestad and M. Tully. 1986. Polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) in human milk: effects of maternal factors and previous lactation. Am. J. Public Health 76:172-177. 440. Rogan, W J., B.C. Gladen, and A J. Wilcox. 1985. Potential reproductive and postnatal morbidity from exposure to polychlorinatedbiphenyls: epidemiologic considerations.Environ. Health Perspect. 60:233-239. 441. Rumsby, P.C., J.G. Evans, H.E. Phillimore, P. Carthew, and A.G. Smith. 1992. Search for Ha-nw codon 61 mutations in liver tumours caused by hexachlorobenzene and Aroclor 1254 in C57BL/10ScSn mice with iron overload. Carcinogenesis 13:1917-1920. 442. Ryan, D.E., P.E. Thomas, D. Korzeniowski, and W. Levin. 1979. Separation and characterization of highly purified forms of liver microsomal cytochrome P-450 from rats treated with polychlorinated biphenyls, phenobarbital, and 3-methylcholanthrene./. Biol. Chem. 254:1365-1374. 443. Ryan, D.E., P.E. Thomas, and W. Levin. 1977. Properties of purified liver microsomal cytochrome P-450 from rats treated with the polychlorinated biphenyl mixture Aroclor 1254. Mol. Pharmacol. 13:521-532. 444. Ryan, D.E., P.E. Thomas, L.M. Reik, and W. Levin. 1982. Purification, characterization and regulation of five rat hepatic cytochrome P-450 isozymes. Xenobiotica 12:727-744. 445. Safe, S. 1984. Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs): biochemistry, toxicology and mechanism of action. CRC Crit. Rev. Toxicol. 12:319-395. 446. Safe, S. 1986. Comparative toxicology and mechanism of action of polychlorinated dibenzo-p-dioxins and dibenzofurans. Annu. Rev. Pharmacol. Toxicol. 26:371-399. 83 447. Safe. S. 1987c. PCBs and human health. In Polychlorinated Biphenyls (PCBs): Mammalian and Environmental Toxicology. Environmental Toxin Series, Vol. 1. S. Safe and O. Hutzinger, editors. Springer-Verlag Publishing Co.. Heidelberg. 133-145. 448. Safe, S. 1989a. Polyhalogenated aromatics: uptake, disposition and metabolism. In Halogenaled Biphenyls, Naphthalene, Dibenzodioxins and Related Compounds.R.D.¥*imbrough and A A. Jensen, editors. Else vier- Norlh Holland, Amsterdam. 51-69. 449. Safe,S. 1989b.PolychJorinatedbiphenyls(PCBs): mutagenicityandcarcinogenicity.A/ufar. Res. 220:31-47. 450. Safe, S. 1990. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). C. R. C. Crit. Rev. Toxicol. 21:51-88. 451. Sate, S. 1991. Polychlorinated dibenzo-/>-dioxins and related compounds: sources, environmental distribution and risk assessment. Environ. Carcin. Ecotox. Reviews C9:261-302. 452. Safe, S. 1988. Polychlorinated biphenyls: human health effects. In Hazards, Decontamination and Replacement of PCBs. J.P. Crin, editor. Plenum Press, New York. 51-69. 453. Safe, S. 1993. Toxicology, structure-function relationships, human and environmental health impacts of polychlorinated biphenyls (PCBs): progress and problems. Environ. Health Perspect. In press. 454. Safe, S., S. Bandiera, T. Sawyer, L. Robertson, A. Parkinson, P.E. Thomas, D.E. Ryan, L.M. Reik, W. Levin, MA. Denomme, and T. Fujita. 1985a. PCBs: structure-function relationships and mechanism of action. Environ. Health Perspect. 60:47-56. 455. Safe, S. and O. Hutzinger (editors). 1987a. Polychlorinated Biphenyls (PCBs): Mammalian and Environmental Toxicology, Environmental Toxin Series. Vol. 1. Springer-Verlag Publishing Co., Heidelberg. 456. Safe, S., G. Mason, T. Sawyer, T. Zacharewski, M. Harris, C. Yao, B. Keyes, K. Farrell, M. Holcomb, D. Davis, L. Safe, J. Piskorska-Pliszczynska, B. Leece, MA. Denomme, O. Hutzinger, H. Thoma, B. Chittim, and J. Madge. 1989c Development and validation of in vitro induction assays for toxic halogenated mixtures. Toxicol. Indust. Health 5:757-775. 457. Safe, S., M. Mullin, L. Safe, C. Pochini, S. McCrindle, and M. Romkes. 1983. High resolution PCB analysis. In Physical Behvior of PCBs in the Great Lakes. D. Mackay, S. Paterson, SJ. Eisenreich, and M.S. Simons, editors. Ann Arbor Science, Ann Arbor, MI. 1-14. 458. Safe, S., L.W. Robertson, L. Safe, A. Parkinson, S. Bandiera, T. Sawyer, and MA. Campbell. 1982. Halogenated biphenyls: molecular toxicology. Con. /. Physiol. Pharmacol. 60:1U57-1064. 459. Safe, S., L. Safe, and M. Mullin. 1985b. Polychlorinated biphenyls (PCBs) - congener-specific analysis of a commercial mixture and a human milk extract. /. Agnc. Food Chem. 33:24-29. 460. Safe, S., L. Safe, and M. Mullin. 1987b. Polychlorinated biphenyls: environmental occurrence and analysis. In Polychlorinated Biphenyls (PCBs): Mammalian and Environment Toxicology, Environmental Toxin Series. Springer-Verlag Publishing Co., Heidelberg. 1-33. 461. Sager, D., D. Girard, and D. Nelson. 1991. Early postnatal exposure to PCBs: sperm function in rats. Environ. Toxicol. Chem. 10:737-746. 84 462. Sager, D.B. 1983. Effect of postnatal exposure to polychlorinated biphenyls on adult male reproductive function. Environ. Res. 31:76-94. 463. Sanders, O.T. and R.L. Kirkpatrick. 1975. Effects of a polychlorinated biphcnyl (PCB) on sleeping times, plasma corticosteroids, and testicular activity of white-footed mice. Environ. Pliysiol. Biochem. 5:308-313. 464. Sanders, O.T., R.L. Zepp, and R.L. Kirkpatrick. 1974. Effect of PCB ingestion on sleeping times, organ weights, food consumption, serum corticostcrone and survival of albino mice. Bull. Em-iron. Contam. Toxicol. 12:394-399. 465. Sangalang, G.B., H.C. Freeman, and R. Crowell. 1981. Testicular abnormalities in cod (Gadus morhua) fed Aroclor 1254. Arch. Environ. Contam. Toxicol. 10:617-626. 466. Sargent, L., Y.P. Dragan, C. Erickson, C J. Laufer, and H.C. Pitot. 1991. Study of the separate and combined effects of the non-planar 2,5, 2',5'- and the planar 3,4,3',4'-tetrachlorobiphenyl in liver and lymphocytes in vivo. Carcinogenesis 12:793-800. 467. Sargent, L.M., G.L. Saltier, B. Roloff, Y-H. Xu, CA. Sattler, L. Meisner, and H.C. Pitot. 1992. Ploidy and specific karyotypic changes during promotion with phenobarbital, 2,5,2',5'-tetrachlorobiphenyl and/or 3,4,3',4'-tetrachlorobiphenyl in rat liver. Cancer Res. 52:955-962. 468. Sassa, S., O. Sugita, N. Ohnuma, S. Imajo, T. Okumura, T. Noguchi, and A. Kappas. 1986. Studies of the influence of chJoro-substituent sites and conformational energy in polychlorinated biphenyls on uroporphyrin formation in chick-embryo liver cell cultures. Biochem. J. 235:291-2%. 469. Sawyer, T. and S. Safe. 1982. PCB isomers and congeners: induction of aryl hydrocarbon hydroxylase and ethoxyresorufin O-deethylase enzyme activities in rat hepatoma cells. Toxicol. Lett. 13:87-94. 470. Sawyer, T.W., A.D. Vatcher, and S. Safe. 1984. Comparative aryl hydrocarbon hydroxylase induction activities of commercial PCBs in Wistar rts and rat hepatoma H-4-II E cells in culture. Chemosphere 13:695-701. 471. Schaeffer, E., H. Greim, and W. Goessner. 1984. Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats. Toxicol. Appl. Pharmacol. 75:278-288. 472. Schantz, S.L., E.D. Levin, and R.E. Bowman. 1991. Long-term neurobehavioral effects of perinatal polychlorinated biphenyl (PCB) exposure in monkeys. Environ. Toxicol. Chem. 10:747-756. 473. Schantz, S.L., E.D. Levin, R.E. Bowman, M.P. Heironimus, and N.K. Laughlin. 1989. Effects of perinatal PCB exposure on discrimination-reversal learning in monkeys. Neurotoxicol. Teratol. 11:243-250. 474. Scheutz, E.G., S.A. Wrighton, S.H. Safe, and P.S. Guzelian. 1986. Regulation of cytochrome P-450p by phenobarbital and phenobarbital-like inducers in adult rat hcpatocytes in primary monolayer culture and in vivo. Biochem. 25:1124-1133. 475. Schmidt, LJ. and R J. Hesselberg. 1992. A mass spectroscopic method for analysis of AHH-inducing and other polychlorinated biphenyl congeners and selected pesticides in fish. Arch. Em-iron. Contam. Toxicol. 23:3'7-44. 476. Schmoldt, A., W. Herzberg, and H.F. Benthe. 1977a. On the inhibition of microsomal drug metabolism by polychlorinated biphenyls (PCBs) and related phenolic compounds. Chem. -Biol. Interact. 16:191-200. 477. Schmoldt, A., E. AJtenahr, W. Grote, H.G. Dammann, B. Sidau, and H.F. Benthe. 1977b. Rat liver changes after subchronic exposition to polychlorinated biphenyls (PCB) of low chlorine content. Arch. Toxicol. 85 37:203-217. 478. Schnellmann. R.G., E.M. Vickers, and I.G. Sipes. 1985. Metabolism and disposilion of polychlorinated biphenyls. In Reviews in Biochemical Toxicology, Vol. 7. E. Hodgson, J.R. Bend, and R.M. Philpot. editors. Elsevicr Press, Amsterdam. 247-282. 479. Schulte-Hermann, R. 1985. Tumor promotion in the liver. Arch. Toxicol. 57:147-158. 480. Schulz, D.E., G. Petrick, and J.C. Duinker. 1989. Complete characterization of polychlorinated biphenyl congeners in commercial Aroclor and Clophen mixtures by multidimensional gas chromalography-electron capture detection. Environ. Sci. Technol. 23:852-859. 481. Seegal, R.F., K.O. Broscn, and B. Bush. 1986a. PolychJorinated biphenyls produce regional alterations of dopamine metabolism in rat brain. Toxicol. Lett. 30:197-202. 482. Seegal, R.F., K.O. Brosch, and B. Bush. 1986b. Regional alterations in serotonin metabolism induced by oral exposure of rats to polychlorinated biphenyls. Neurotoxicology 7:155-166. 483. Seegal, R.F., B. Bush, and K.O. Brosch. 1991. Comparison of effects of Aroclors 1016 and 1260 on non-human primate catecholamine function. Toxicology 66:145-163. 484. Seegal, R.F., B. Bush, and W. Shain. 1990. Lightly chlorinated on/io-substituled PCB congeners decrease dopamine in nonhuman primate brain and in tissue culture. Toxicol. Appl. Pharmacol. 106:136-144. 485. Sepkovic, D.W. and JJ. Byrne. 1984. Kinetic parameters of L-^IJtriiodothyronine degradation in rats pretreated with polyhalogenated biphenyls. Fa, Chem. Toxic. 22:743-747. 486. Serabjit-Singh, CJ., P.W. Albro, I.G.C. Robertson, and R.M. Philpot. 1983. Interactions between xenobiotics that increase or decrease the levels of cytochrome P-450 isozymes in rabbit lung and liver. /. Biol. Chem. 258:12827-12834. 487. Shain, W., B. Bush, and R. Seegal. 1991. Neurotoxicity of polychlorinated biphenyls: structure-activity relationship of individual congeners. Toxicol. Appl. Pharmacol. 111:33-42. 488. Shelton, D.W., D.E. Goeger, J.D. Hendricks, and G.S. Bailey. 1986. Mechanisms of anti-carcinogenesis: the distribution and metabolism of aflatoxin B, in rainbow trout fed Aroclor 1254. Carcinogenesis 7:1065-1071. 489. Shelton, D.W., J.D. Hendricks, R.A. Coulombe, and G.S. Bailey. 1984. Effect of dose on the inhibition of carcinogenesis/mutagenesis by Aroclor 1254 in rainbow trout fed aflatoxin B,./. Toxicol. Environ. Health 13:649-657. 490. Shimada, T. 1976. Metabolic activation of [MC]polychlorinated biphenyl mixtures by rat liver microsomes. Bull. Environ. Contain. Toxicol. 16:25-32. 491. Shimada, T. and R. Sato. 1978. Covalent binding in vitro of polychlorinated biphenyls to microsomal macromolecules. Biochem. Pharmacol. 27:585-593. 492. Shu, H.P., DJ. Paustenbach, and FJ. Murray. 1987. A critical evaluation of the use of mutagenesis, carcinogenesis, and tumor promotion data in a cancer risk assessment of 23,7,8-tetrachlorodibenzo-p-dioxin. Regulat. Toxicol. Pharmacol. 7:57-88. 493. Silberhorn, E.M., M.P. Glauert, and L.W. Robertson. 1990. Carcinogenicity of polyhalogenated biphenyls: PCBs and PBBs. CRC Crit. Rev. Toxicol. 20:439-4%. 86 494. Silkworth, J.B., L. Antrim, and L.S. Kaminsky. 1984. Correlations between polychlorinated biphenyl immunotoxicity, the aromatic hydrocarbon locus and liver microsomal enzyme induction in C57BL/6 and DBA/2 mice. Toxicol. Appl. Pharmacol. 75:156-165. 495. Silkworth, J.B. and E.M. Grabstein. 1982. Polychlorinated biphenyl immunotoxicity: dependence on isomer planarity and Ah gene complex. Toxicol. Appl. Pharmacol. 65:109-115. 4%. Silkworth, J.B. and L.D. Loose. 1978. Cell-mediated immunity in mice fed either Aroclor 1016 or hexachlorobenzene. Toxicol. Appl. Pharmacol. 45:326. Abstract. 497. Sinclair, P.R., WJ. Bement, H.L. Bonkovsky, R.W. Lambrecht, J.E. Frezza, J.F. Sinclair, AJ. Urquhart, and G.H. Elder. 1986. Uroporphyrin accumulation produced by halogenated biphenyls in chick-embryo hepatocytes. Biochem. J. 237:63-71. 498. Sinclair, P.R., WJ. Bement, H.L. Bonkovsky, and J.F. Sinclair. 1984. Inhibition of uroporphyrinogen decarboxylase by halogenated biphenyls in chick hepatocyte cultures: essential role for induction of cytochrome P-448. Biochem. J. 222:737-748. 499. Sinclair, P.R., WJ. Bement, R.W. Lambrecht, N. German, and J.F. Sinclair. 1990. Chlorinated biphenyls induce cytochrome P450LA2 and uroporphyrin accumulation in cultures of mouse hepatocytes. Arch. Biochem. Biophys. 281:225-232. 500. Sipes, I.G. and R.G. Schnellmann. 1987. Biotransformation of PCBs: metabolic pathways and mechanisms. InPofychlorinated Biphenyls (PCBs): Mammalian and Environental Taricolofy. Environmental Toxin Series. S. Safe and O. Hutzinger, editors. Springer-Verlag Publishing Co., Heidelberg. 97-110. 501. Sissons, D. and D. WeltL 1971. Structural identification of polychlorinated biphenyls in commercial mixtures by gas liquid chromatography, nuclear magnetic resonance and mass spectrometry. /. Chromatogr. 60:15-32. 502. Skaare, J.U., E.G. Jensen, A. Goksoyr, and E. Egaas. 1991. Response of xenobiotic metabolizing enzymes of rainbow trout (Oncorhynchus mytoss) to the mono-ortho substituted polychlorinated PCB congener, 2,3',4,4',5-pentachlorobiphenyl, PCB-118, detected by enzyme activities and immunochemical methods. Arch. Environ. Contam. Toxicol. 20:349-352. 503. Smialowicz, RJ., J.E. Andrews, M.M. Riddle, R.R. Rogers, R.W. Luebke, and C.B. Copeland. 1989. Evaluation of the immunotoxicity of low level PCB exposure in the rat. Toxicology 56:197-211. 504. Smith, A.G., J.E. Francis, and P. Carthew. 1990a. Iron as a synergist for hepatocellular carcinoma induced by polychlorinated biphenyls in Ah -responsive C57BL/10ScSn mice. Carcinogenesis 11:437-444. 505. Smith, A.G., J.E. Francis, J A. Green, J.B. Greig, C.R. Wolf, and M.M. Manson. 1990b. Sex-linked hepatic uroporphyria and the induction of cytochromes P450IA in rats caused by hexachlorobenzene and polyhalogenated biphenyls. Biochem. Pharmacol. 40:2059-2068. 506. Smith, JA.B., J. Schloemer, L.K. Lowry, A.W. Smallwood, R.N. Ligo, S. Tanaka, W. Stringer, M. Jones, R. Hervin, and CJ. Glueck. 1982. Metabolic and health consequences of occupational exposure to polychlorinated biphenyls (PCBs). Brit. J. Ind. Med. 39:361-369. 507. Snyder, R. and H. Remmer. 1979. Classes of hepatic microsomal mixed function oxidase inducer. Pharmacol. Therap. 7:203-244. 508. Solt, D.B. and E. Farber. 1976. New principle for the analysis of chemical carcinogenesis. Nature 263:702-703. 87 509. Sonzogni, W., L. Maack, T. Gibson, and J. Lawrence. 1991. Toxic polychlorinated biphenyl congeners in Sheboygan River (USA) sediments. Bull. Environ. Contam. Toxicol. 47:398-405. 510. Spear, PA., D.H. Bourbonnais, D.B. Peakall, and T.W. Moon. 1989. Dove reproduction and retinoid (vitamin A) dynamics in adult females and their eggs following exposure to 3.3',4,4'-tetrachlorobiphenyl. Can. J. Zool. 67:908-913. 511. Spear, PA. and T.W. Moon. 1985. Low dietary iodine and thyroid anomalies in ring doves, Streptopelia risoria, exposed to 3,4,3',4'-tetrachlorobiphenyl. Arch. Environ. Contam. Toxicol. 14:547-553. 512. Spear, PA., T.W. Moon, and D.B. Peakall. 1986. Liver retinoid concentrations in natural populations of herring gulls (Larus argentatus) contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin and in ring doves (Streptopelia risoia) injected with a dioxin analogue. Can. J. Zool. 64:204-208. 513. Spencer, F. 1982. An assessment of the reproductive toxic potential of Aroclor 1254 in female Sprague-Dawley rats. Bull. Environ. Contam. Toxicol. 28:290-297. 514. Stadnicki, S., F.S.D. Lin, and J.R. Alien. 1979b. DNA single strand breaks caused by 2,2',5,5'- tetrachlorobiphenyl and its metabolites. Res. Commun. Chem. Pathol. Pharmacol. 24:313-327. 515. Stadnicki, S.S. and J.R. Alien. 1979b. Toxicity of 2,2',5,5'-tetrachlorobiphenyl and its metabolites, 2,2',5,5'- tetrachlorobiphenyl-3,4-oxide and 2,2',5,5'-tetrachlorobiphenyl-4-ol to cultured cells in vitro. Bull. Environ. Contam. Toxicol. 23:788-7%. 516. Stegeman, J Jn R.M. Smolowitz, and M.E. Hahn. 1991. Immunohistochemical localization of environmentally- induced cytochrome P450LA1 in multiple organs of the marine telcostStenotomus chrysops (Scup). Toxicol. Appl. Pharmacol. 110:486-504. 517. Steinberg, K.K., L.WJ. Freni-Titulaer, T.N. Rogers, V.W. Burse, P.W. Mueller, PA. Stohr, and D.T. Miller. 1986. Effects of polychlorinated biphenyls and lipemia on serum analytes./. Toxicol. Environ. Health 19:369-381. 518. Stehr-Green, PA., V.W. Burse, and E. Welty. 1988. Human exposure to polychlorinated biphenyls at toxic waste sites: investigations in the United States. Arch. Environ. Health 43:420-424. 519. Stehr-Green, PA., D. Ross, J. Liddle, E. Welty, and G. Steele. 1986. A pilot study of serum polychlorinated biphenyl levels in persons at high risk of exposure in residential and occupational environments. Arch. Environ. Health 41:240-244. 520. Stonard, M.D. and J.B. Grieg. 1976. Different patterns of hepatic microsomal enzyme activity produced by administration of pure hexachlorobiphenyi isomers and hexachlorobenzene. Chem. -Bioi. Interact 15:365- 379. 521. Storr-Hansen, E. and T. Cederberg. 1992. Determination of coplanar polychlorinated biphenyl (CB) congeners in seal tissues by chromatography on active carbon, dual-column high resolution GC/ECD and high resolution OC/high resolution MS. Chemosphere 24:1181-1196. 522. Stratton, C.L. and J.B. Sosebee,Jr.. 1976. PCB and PCT contamination of the environment near sites of manufacture and use. Bull. Environ. Contam. Toxicol. 10:1229-1223. 523. Street, J.C. and R.P. Sharma. 1975. Alteration of induced cellular and humoral immune responses by pesticides and chemicals of environmental concern: quantitative studies of immunosuppression by DDT, 88 Aroclor 1254, carbaryl, carbofuran, and methyl parathion. Toxicoi Appl. Pharmacol. 32:587-602. 524. Sundheimer, D.W., M.B. Caveness, and J A. Goldstein. 1983. Differential metabolism of acetanilide versus ethyoxycoumarinandbenzo[a]pyrenebytwo3-methyicholanthrene-inducibleformsofratlivercytochrome P-450. Arch. Biochem. Biophys. 226:548-557. 525. Sundstrom, G., O. Hutzinger, and S. Safe. 1976. The metabolism of chlorobiphenyls - a review. Chemosphere 5:267-298. 526. Swain, M.G., S.B. Follows, and G.S. Marks. 1983. Inhibition of uroporphyrinogen decarboxylase by 3,3',4,4'- tetrachlorobiphenyl in chick embryo liver cell culture. Can. J. Physiol. Pharmacol. 61:105-108. 527. Takabatake, E., M. Fujita, and Y. Sawa. 1980. Combined effects of polychlorinated biphenyls and methylmercury on hepatic microsomal monoxygenases and the hepatotoxic action of bromobenzene. /. Pharm. Dyn. 3:463-469. 528. Takagi, Y., S. Aburada, T. Otake, and N. Ikegami. 1987. Effect of polychlorinated biphenyls (PCBs) accumulated in the dam's body on mouse filial immunocompetence..4/c/i. Environ. Contain. Toxicoi. 16:375- 381. 529. Tanabe, S. 1989a. A need for revaluation of PCB toxicity. Marine Pollution Bulletin 20:247-248. 530. Tanabe, S., H. Hidaka, and R. Tatsukawa. 1983. PCBs and chlorinated hydrocarbon pesticides in Antarctic atmosphere and hydrosphere. Chemosphere 12:277-288. 531. Tanabe, S., N. Kannan, M. Ono, and R. Tatsukawa. 1989b. Toxic treat to marine mammals: increasing toxic potential of aon-ortho and moao-ortho coplanar PCBs from land to ocean. Chemosphere 18:485-490. 532. Tanabe, S., N. Kannan, A. Subramanian, S. Watanabe, M. Ono, and R. Tatsukawa. 1987b. Occurrence and distribution of toxic coplanar PCBs in the biota. Chemosphere 16:1965-1970. 533. Tanabe, S., N. Kannan, A. Subramanian, S. Watanabe, and R. Tatsukawa. 1987b. Highly toxic coplanar PCBs: occurrence, source, persistency and toxic implications to wildlife and humans. Environ. Pollution 47:147-163. 534. Tanabe, S., N. Kannan, T. Wakimoto, and R. Tatsukawa. 1987c. Method for the determination of three toxic non-ort/iochlorine substituted coplanar PCBs in environmental samples at part-per-trillion levels. Intern. J. Environ. Anal. Chem. 29:199-213. 535. Tanabe, S., N. Kannan, T. Wakimoto, and R. Tatsukawa. 1989c. Isomer-specific determination and toxic evaluation of potentially hazardous coplanar PCBs, dibenzofurans and dioxins in the tissues of "Yusho" PCB poisoning victim and in the causal oil. Toxicoi. Environ. Chem. 24:215-231. 536. Tanimura, T., M. Etna, and T. Kihara. 1980. Effects of combined treatment with methylmercury and polychlorinated biphenyls (PCBs) on the development of mouse offspring. Sch. Med. 4:163-198. 537. Tarhanen, J., J. Koistinen, J. Paasivirta, P J. Vuorinen, J. Koivusaari, I. Nuuja, N. Kannan, and R. Tatsukawa. 1989. Toxic significance of planar aromatic compounds in Baltic ecosystem - new studies on extremely toxic coplanar PCBs. Chemosphere 18:1067-1077. 538. Tateraatsu, K., K. Nakanishi, G. Murasaki, Y. Miyata, M. Hirose, and N. Ito. 1979. Enhancing effect of inducers of liver microsomal enzymes on induction of hyperplastic liver nodules by /V-2-fluorenylacetamide in rats./. Natl. CancerInst. 63:1411-1416. 89 539. Taylor, P.R., C.E. Lawrence, H-L. Hwang, and A.S. Paulson. 1984. Polychlorinated biphenyis: influence on birthweight and gestation. Am. J. Public Health 74:1153-1154. 540. Taylor, P.R., J.M. Stelma. and C.E. Lawrence. 1989. The relation of polychlorinated biphenyls to birlh weight and gestational age in the offspring of occupationally exposed mothers. Am. J. Epidemiol. 129:395-406. 541. Thomas, P.E., D. Korzeniowski, D.E. Ryan, and W. Levin. 1979. Preparation of monospecific antibodies against two forms of rat liver cytochrome P-450 and quantitation of these two antigens in microsomes. Arch. Biochem. Biophys. 192:524-532. 542. Thomas, P.E., L.M. Reik, D.E. Ryan, and W. Levin. 1981. Regulation of three forms of cytochrome P-450 and epoxide hydrolase in rat liver microsomes: effects of age, sex and induction./ Biol. Chem. 256:1044-1052. 543. Thomas, P.E., L.M. Reik, D.E. Ryan, and W. Levin. 1983. Induction of two immunochemically related rat liver cytochrome P-450 isozymes, cytochromes P-450c and P-450d, by structurally diverse xenobiotics. /. Biol. Chem. 258:4590-4598. 544. Thomas, P.T. and R.D. Hinsdill. 1978. Effect of polychlorinated biphenyls on the immune responses of rhesus monkeys and mice. Toadcol. Appl. Pharmacol. 44:41-51. 545. Tillitt, D.E., G.T. Ankley, J.P. Giesy, J.P. Ludwig, H. Kurita-Matsuba, D.V. Weseloh, P.S. Ross, CA. Bishop, L. Sileo, K.L. Stromborg, J. Larson, and TJ. Kubiak. 1992. Polychlorianted biphenyl residues and egg mortality in double crested cormorants from the Great Lakes. Environ. Toxicol. Chem. 11:1281-1288. 546. Tillitt, D.E., J.P. Giesy, and G.T. Ankley. 1991. Characterization of the H4IIE rat hepatoma cell bioassay as a tool for assessing toxic potency of planar halaogenated hydrocarbons in environmental samples. Environ. Sci. Technol. 25:87-92. 547. Tilson, HA., G J. Davis, J A. Mclachlan, and G.W. Lucier. 1979. The effects of polychlorinated biphenyls given prenatally on the neurobehavioral development of mice. Environ. Res. 18:466-474. 548. Tilson, HA., J.L. Jacobson, and W J. Rogan. 1990. Polychlorinated biphenyls and the developing nervous system: cross-species comparisons. Neurotoxicol. Teratol. 12:239-248. 549. Traber, P.G., J. Chianale, R. Florence, K. Kim, E. Wojcik, and J J. Gumucio. 1988. Expression of cytochrome P450b and P450e benes in small intestinal mucosa of rats following treatment with phenobarbital, polyhalogenated biphenyls, and organochlorine pesticides. /. Biol. Chem. 263:9449-9455. 550. Trotter, WJ., SJ.V. Young, J.L. Casterline,Jr., JA. Bradlaw, and L.R. Kamps. 1982. Induction of aryl hydrocarbon hydroxylase activity in cell cultures by Aroclors, residues from Yusho oil samples, and polychlorinated biphenyl residues from fish samples. /. Assoc. Off. Anal. Chem. 65:838-844. 551. Truelove, J_ D. Grant, J. Mes, H. Tryphonas, L. Tryphonas, and Z. Zawidzka. 1982. Polychlorinated biphenyl toxicity in the pregnant cynomolgus monkey: a pilot study. Arch. Environ. Contam. Toxicol. 11:583-588. 552. Tryphonas, H., S. Hayward, L. O'Grady, J.C.K. Loo, D.L. Arnold, F. Bryce, and Z.Z. Zawidzka. 1989. Immunotoxicity studies of PCB (Aroclor 1254) in the adult rhesus (Macaca mulatto] monkey - preliminary report. Int. J. Immunopharmac. 11:199-206. 553. Tryphonas, H., M.I Luster, G. Schiffman, L-L. Dawson, M. Hodgen, D. Germolec, S. Hayward, F. Bryce, J.C.K. Loo, F. Mandy, and D.L. Arnold. 1991a. Effect of chronic exposure of PCB (Aroclor 1254) on specific and nonspecific immune parameters in the rhesus (Macaca mulatto) monkey. Fund. Appl. Toxicol. 90 16:773-786. 554. Tryphonas, H., M.I. Luster, K.L. White, P.H. Naylor, M.R. Erdos, G.R. Burlesoa, D. Germolec, M. Hodgen, S. Hayward, and D.L. Arnold. 1991b. Effects of PCB (Aroclor-1254) on non-specific immune parameters in rhesus (Macaca mulatto) monkeys. Int. J. Immunopharmacol. 13:639-648. 555. Tryphonas, L., D.L. Arnold, Z. Zawidzka, J. Mes, S. Charbonneau, and J. Wong. 1986b. A pilot study in adult rhesus monkeys (A/, mulatto) treated with Aroclor 1254 for two years. Toxicol. Pathol. 14:1-10. 556. Tryphonas, L., S. Charbonneau, H. Tryphonas, Z. Zawidzka, J. Mes, J. Wong, and D.L. Arnold. 1986a. Comparative aspects of Aroclor 1254 toxicity in adult cynomolgus and rhesus monkeys: a pilot study. Arch. Environ. Contain. Toxicol. 15:159-169. 557. Ueng, T-H. and A.P. Alvares. 1981. Selective loss of pulmonary cytochrome P-450, in rabbits pretreated with polychlorinated biphenyls. /. Biol. Chem. 256:7536-7542. 558. Ueng, T-H. and A.P. Alvares. 1985. Selective induction and inhibition of liver and lung cytochrome P-450- depcndent monoxygenases by the PCBs mixture, Aroclor 1016. Toxicology 35:83-94. 559. Ueng, T-H., J.L. Eiseman, and A.P. Alvares. 1980. Inhibition of pulmonary cytochrome P-450 and benzo(a)pyrene hydroxylase in rabbits by polychlorinated biphenyls (PCBs). Biochem. Biophys. Res. Comm. 95:1743-1749. 560. United States Environmental Protection Agency, 1991. Workshop Report on Toxicity Equivalency Factors for Polychlorinated Biphenyl Congeners. Risk Assessment Forum, EPA/625/3-91/020. 561. Van Birgelen, A., J. Van der Kolk, K. Fase, H. Poiger, A. Brouwer, and M. Van den Berg. 1992. Toxicity and biochemical potencies of polychlorinated biphenyl congeners relative to 23,7,8-tetrachlorodibenzo-/>-dioxin in three month feeding studies in the rat. Organohalogen Compounds, Dioxin '92 10:373-376. Abstract. 562. Van den Berg, KJ., C. Zurcher, and A. Brouwer. 1988. Effects of 3,4,3',4'-tetrachlorobiphenyl on thyroid function and histology in marmoset monkeys. Toxicol. Lett. 41:77-86. 563. Villeneuve, D.C., D.L. Grant, K. Khera, D J. Clegg, H. Baer, and W.EJ. Phillips. 1971a. The fetotoxicity of a polychlorinated biphenyl mixture (Aroclor 1254) in the rabbit and in the rat. Environ. Physiol. 1:67-71. 564. Villeneuve, D.C., D.L. Grant, W.EJ. Phillips, M.L. Clark, and DJ. Clegg. 1971b. Effects of PCB administration on microsomal enzyme activity in pregnant rabbits. Bull. Environ. Contain. Toxicol. 6:120-128. 565. Vos, J.G. and RJ3. Beems. 1971. Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof in rabbits. Toxicol. Appl. Pharmacol. 19:617-633. 566. Vos, J.G. and T. DeRoij. 1972. Immunosuppressive activity of a polychlorinated biphenyl preparation en the humoral immune response in guinea pigs. Toxicol. Appl. Pharmacol. 21:549-555. 567. Vos, J.G. and H. Van Genderen. 1973. Toxicological aspects of immunosuppression. In Pesticides in the Environment. A Continuing Controversy. W.B. Deichman, editor. 8th Int. Conf. Toxicol. Occup. Med., Intercontinental Medical Book Co., New York. 527-545. 568. Voss, S.D., D.W. Shelton, and J.D. Hendricks. 1982. Effects of dietary Aroclor 1254 and cyclopropene fatty acids on hepatic enzymes in rainbow iroul.Arch. Environ. Contam. Toxicol. 11:87-91. 569. Walker, M.K. and R.E. Peterson. 1991. Potencies of polychlorinated dibenzo-p-dioxin, dibenzofuran, and 91 biphenyl congeners, relative to 2,3,7,8-tetrachlorodibenzo-/»-dioxin, for producing early life stage mortality in rainbow trout (Oncorhynchus mykiss). Aquatic Toxicology 21:219-238. 570. Ward, J.M. 1985. Proliferative lesions of the glandular stomach and liver in F344 rats fed diets containing Aroclor 1254. Environ. Health Perspect. 60:89-95. 571. Ward, J.M., H. Tsuda, M. Tatematsu, A. Hagiwara, and N. Ito. 1989. Hepatotoxicity of agents that enhance formation of focal hepatoceilular proliferative lesions (putative preneoplastic foci) in a rapid rat liver bioassay. Fund. Appl. Toxicol. 12:163-171. 572. Warshaw, R., A. Fischbein, J. Thornton, A. Miller, and IJ. Selikoff. 1979. Decrease in vital capacity in PCB-exposed workers in a capacitor manufacturing facility. Ann. N. Y. Acad. Sci. 320:277-283. 573. Wasserrnan, M., D. Wasserman, S. Cucos, and H J. Miller. 1979. World PCBs map: storage and effects in man and his biologic environment in the 1970s. Ann. N. Y. Acad. Sci. 320:69-124. 574. Watanabe, M. and T. Sugahara. 1981. Experimental formation of cleft palate in mice with polychlorinated biphenyls (PCBs). Toxicology 19:49-53. 575. Webb, R.G. and A.C. McCaU. 1973. Quantitative PCB standards for electron capture gas chromatography. /. Chromatogr. Sci. 11:366-373. 576. Whitlock, J.P.Jr. 1986. The regulation of cytochrome P-450 gene expression. Annu. Rev. Pharmacol. Tcodcol. 26:333-369. 577. Whitlock, J.P. Jr. 1987. The regulation of gene expression of 23,7,8-tetrachlorodibenzo-/7-dioxin. Pharmacol. Rev. 39:147-161. 578. Whitlock, J.P. Jr. 1990. Genetic and molecular aspects of 2,3,7,8-tetrachlorodibenzo-/7-dioxin action.^ln/ju. Rev. Pharmacol. Toxicol. 30:251-277. 579. Williams, D.T. and G.L. LeBel. 1991. Coplanar polychlorinated biphenyl residues in human adipose tissue samples from Ontario municipalities. Chemosphere 22:1019-1028. 580. Williams, L.L. and J.P. Giesy. 1992a. Relationships among concentrations of individual polychlorinated biphenyl (PCB) congeners, 23,7,8-tetrachlorodibenzo-/>-dioxin equivalents (TCDD-EQ) and rearing mortality of chinook salmon (Oncorhynchus tshawytscha) eggs from Lake Michigan./. Great Lakes Res. 18:108-124. 581. Williams, L.L., J.P. Giesy, N. DeGalan, DA. Verbrugge, D.E. Tillitt, G.T. Ankley, and R.L. Welch. 1992b. Prediction of concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents from total concentrations of polychlorinated biphenyls in fish fillets. Environ. Sci. Technol. 26:1151-1159. 582. Wolff, M.S. 1985. Occupational exposure to polychlorinated biphenyls (PCBs). Environ. Health Perspect. 60:D3-138. 583. Wolff, M.S., A. Fischbein, J. Thornton, C. Rice, R. Lilis, and IJ. Selikoff. 1982. Body burden of polychlorinated biphenyls among persons employed in capacitor manufacturing. Int. Arch. Occup. Environ. Health 49:199. 584. Wong, A., P.K. Basrur, and S. Safe. 1979. The metabolically mediated DNA damage and subsequent repair by 4-chlorobiphenyl in Chinese hamster ovary cells. Res. Common. Chem. Pathol. Pharmacoi. 24:543- 570. 92 585. Wong, T.K., P-L. Chiu, P.P. Fu, and S.K. Yang. 1981. Metabolic study of 7-methylbenzo(alpyrene with rat liver microsotnes: separation by reversed-phase and normal-phase high performance liquid chromatography and characterization of metabolites. Chem. -Biol. Interact. 36:153-166. 586. Wyndham, C. and S. Safe. 1978. In vitro metabolism of 4-chlorobiphenyl by control and induced rat liver microsomes. Biochemistry 17:208-215. 587. Yamamoto, H. and H. Yoshimura. 1973. Metabolic studies on polychlorinated biphenyl. III. Complete structure and acute toxicity of the metabolites of 2,4,3,4'-tetrachlorobiphenyl. Chem. Pharm. Bull. 21:2237-2242. 588. Yamamoto, H., H. Yoshimura, M. Fujita, and T. Yamamoto. 1976. Metabolic and toxicologic evaluation of 23,3',4,4'-pentachlorobiphenyl in rats and mice. Chem. Pharm. Bull. 24:2168-2174. 589. Yao, C, B. Panigrahy, and S. Safe. 1990. Utilization of cultured chick embryo hepatocytes as in vitro bioassays for polychlorinatedbiphenyis(PCBs):quanQtaUvestruOure-mducdonrelaUonships.C^errjo5pA«/ie 21:1007-1016. 590. Yeowell, H.N, D J. Waxman, G A. LeBlanc, P. Linko, and J A Goldsiein. 1989. Suppression of male-specific cytochrome P450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl in rat liver is not causally related to changes in serum testosterone. Arch. Biochem. Biophys. 271:508-514. 591. Yeowell, H.N., DJ. Waxman, A. Wadhera, and JA. Goldstein. 1987. Suppression of the constitutive, male-specific rat hepatic cytochrome P-450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl and 3- methylcholanthrene. Mol. Pharmacol. 32:340-347. 592. Yoshihara, S., K. Kawano, H. Yoshimura, H. Kuroki, and Y. Masuda. 1979. lexicological assessment of highly chlorinated biphenyl congeners retained in the Yusho patients. Chemosphere 8:531-538. 593. Yoshihara, S., K. Nagata, I. Wada, H. Yoshimura, H. Kuroki, and Y. Masuda. 1982. A unique change of steroid metabolism in rat liver microsomes induced with highly toxic polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF). /. Pharm. Dyn. 5:994-1004. 594. Yoshihara, S., K. Nagata, and H. Yoshimura. 1983. Different responsiveness of hepatic and pulmonary microsomal mixed function oxidases to phenobarbital-type and 3-methylcholanthrene-type polychlorinated biphenyls in rats. /. Pharm. Dyn. 6:954-962. 595. Yoshimura, H., N. Ozawa, and S. Saeki. 1978. Inductive effect of polychlorinated biphenyls mixture and individual isomers on the hepatic microsomal enzymes. Chem. Pharm. Bull. 26:1215-1221. 596. Yoshimura, H., Y. Yonemoto, H. Yamada, N. Koga, K. Oguri, and S. Saeki. 1987. Metabolism in vivo of 3,43',4'-tetrachlorobiphenyl and lexicological assessment of the metabolites in rais.Xenobiotica 17:897-910. 597. Yoshimura, H., S. Yoshihara, N. Ozawa, and M. Miki. 1979. Possible correlation between induction modes of hepatic enzymes by PCBs and their toxicity in rats. ^nn. N. Y. Acad. Sci. 320:179-182. 598. Yu, M-L., C-C. Hsu, B.C. Gladen, and WJ. Rogan. 1991. In utero PCB/PCDF exposure: relation of developmental delay to dysmorphology and dose. Neurotoxicol. Teratol. 13:195-202. 599. Zack, TA. and D.C. Musch. 1979. Mortality of PCB workers at the Monsanto Plant in Sanget, Illinois. Monsanto Internal Report, St. Louis. 600. Zinld, J.G. 1977. Skin and liver lesions in rats fed a polychlorinated biphenyl mixture. Arch. Environ. Contam. 93 ToxicoL 5:217-228. 94 Table 1. Quantitative and qualitative analysis of PCBs on Aroclor 1260 and extracts from human milk samples (Safe, 1985b; Duarte-Davidson, 1991). Congener % in % of Total PCBs Congener % in % of Total PCBs Name' Aroclor 1260 in Human Milkb Name1 Aroclor 1260 in Human Milk" PCB-015 9.4 PCB-118 0.49 6.5 4.2 PCB-018 0.12 . . . 4.3 PCB-134 0.35 ... PCB-017 0.05 PCB-114 . . . 0.33 PCB-024 0.01 . . . PCB-131 0.07 ... PCB-016 0.04 ... PCB-122 0.12 0.53 PCB-029 0.02 PCB-146 13 1.9 PCB-026 0.02 PCB-153 9.6 12.0 12.7 PCB-028 0.04 8.8 4.7 PCB-141 2.5 0.29 PCB-021 0.01 ... PCB-176 0.33 PCB-033 0.09 2.2 PCB-137 0.22 0.87 PCB-053 0.04 ... PCB-130 0.59 PCB-022 0.01 0.65 PCB-138 6.5 10.0 10.1 PCB-045 0.07 ... PCB-158 0.70 0.55 PCB-046 0.02 0.25 PCB-129 0.20 PCB-052 0.25 1.9 3.9 PCB-178 1.2 ... PCB-043 0.02 ... PCB-175 0.49 ... PCB-049 0.06 0.66 PCB-187 4.5 1.5 6.3 PCB-048 0.29 0.37 PCB-183 2.3 1.4 1.2 PCB-044 0.11 0.78 1.8 PCB-128 0.47 0.33 0.8 PCB-037 0.04 2.9 PCB-167 0.16 0.85 PCB-042 0.04 PCB-185 4.1 0.11 PCB-041 0.25 1.3 PCB-174 5.5 0.39 PCB-040 0.03 PCB-177 1.9 0.61 PCB-100 0.02 ... PCB-171 + 202 1.2 0.37 PCB-074 0.03 11.0 3.r PCB-156 0.45 4.87 2.5' PCB-070+076 0.15 0.61 PCB-173 0.06 PCB-095 2.7 ... PCB-200 0.78 PCB-091 0.07 PCB-157 0.47 PCB-056+060 0.14 0.71 PCB-172 0.78 0.31 PCB-084 0.65 ... PCB-180 9.1 5.3 11.1 PCB-101 2.5 0.97 2.2 PCB-193 0.47 0.19 PCB-099 0.13 4.8 4.0 PCB-191 0.10 0.90 PCB-119 0.08 1.9 PCB-199 0.33 ... PCB-083 0.04 PCB-170 6.8 5.3 3.5 PCB-097 0.45 PCB-201 2.9 0.85 1.8 PCB-087 0.45 0.82 PCB-203 3.1 0.79 PCB-085 0.13 ... PCB-1% 2.5 0.18 PCB-136 1.4 ... PCB-189 0.15 2.4 PCB-110 1.7 1.0 1.3d PCB-195 3.1 OJ1 PCB-154 0.02 PCB-207 0.080 PCB-082 0.11 ... PCB-194 1.7 0.48 PCB-151 2.5 0.59 0.9* PCB-205 0.11 0.06 0.7« PCB-144+D5 1.5 0.51 PCB-206 0.85 0.24 PCB-107 0.03 0.31 PCB-209 0.06 0.09 PCB-149 7.4 ... 1.8 Congener names adapted from Ballschmiter (1980). Human milk sample collected and extraced by Michigan Department of Public Health under Cooperative Agreement CR807192 with the Large Lakes Research Station, U.S. Environmental Protection Agency. 61/74 combined;d 77/110 combined;' 82/151 combined; ' 156/202 combined; * 194/205 combined. 95 Table 2. Relative concentrations of coplanar PCBs in human milk and adipose tissue samples. Congener and Concentration (ng/g) Samples 3,3',4,4'- 3,3',4,4'5- 3,3',4,4',5,5'- Reference(s) (77)' (126)' (169)' Upstate New York 0.16 - 0.49 non-detectable non-detectable Hong, 1992 (milk) Ontario (adipose non-detectable 0.124 - 0.303 0.113 - 0.198 Williams, 1991 tissue) Quebec (milk) 0.008 0.081 0.032 DewaiUy, 1991 Japan (adipose 0.094 - 0.86 0.12 - 0.73 0.036 - 0.20 Kannan, 1989 tissue) 96 Table 3. Effects of PCBs on occupationally-exposed workers. Effects References Chloracne and related dermal lesions Hara, 1985 Ouw, 1976 Fischbein, 1979 Maroni, 1981 Diverse hepatic responses including hepatomegaly, increased liver and Hara, 1985 serum enzymes and lipid, induction of drug-metabolizing enzymes Ouw, 1976 Fischbein, 1979, 1983 Chase, 1982 Lawton, 1985 Steinberg, 1980 Alvares, 19T7b Smith, 1982 Emmett, 1985 Decreases in pulmonary function Warshaw, 1979 Decrease birth weight in offspring of occupationally-exposed mothers Taylor, 1984, 1989 Eye irritation Hara, 1985 No increased mortality Brown, 1981, 1987 Variable effects on cancer formation Gustavsson, 1986 Silberhorn, 1990 Bertazzi, 1987 Bahn, 1976, 1977 Davidorf, 1979 Zack, 1979 Table 4. Toxicity of commercial PCBs. Response PCB Mixture Species Reference Lethality LDX, 1.14, 1.30 ml/kg (F, M) Kanechlor 400 Rat Kimbrough, 1978 LDX, 1.05, 1.15 g/kg (F, M) Kanechlor 300 LDW, 4.25 g/kg (M) Aroclor 1242 Rat Bruckner, 1973; Kimbrough, 1978 LDX, 1.3-25 g/kg (M, F / age-dependenl) Aroclor 1254 Rat Grant, 1974 LDX, 0.358- 10 g/kg (M.F) Aroclors 1254 and 1260 Rat Linder, 1974 LD*, 4.0 g/kg (F) Aroclor 1221 Rat Nelson, 1972 LD*, 11.3g/k/g(F) Aroclor 1260 LD*. 1.57-1.875 g/kg (F, M) Kanechlor 400 Mouse Kimbrough, 1978 LDX, 0.8-1.2 g/kg Aroclor 1254 Mouse Lewin, 1972 LDX, 2.0-3.17 g/kg Aroclor 1221 Rabbit Nelson, 1972 LD*,, 1.26-2.0 g/kg Aroclor 1232 LDX, 0.79-1.27 g/kg Aroclor 1242 LDso, 0.79-1.27 g/kg Aroclor 1248 LDM) 1.26-2.0 g/kg Aroclor 1260 LD,,,, 1.26-3.16 g/kg Aroclor 1262 LD,,,, 2.5 g/kg Aroclor 1268 LD*, 0.5-4.0 g/kg Aroclors 1221, 1242 and 1254 Mink Auerlich, 1977; Hornshaw, 1986 Reproductive Toxicitv Effect on fetal viability Aroclor 1254 Rabbit Villeneuve, 1971a,b Fetal toxicity Aroclor 1254 Monkey Truelove, 1982 Severe reproductive failure Aroclor 1242 Mink Bleavins, 1980 Table 4. cont'd. Response PCB Mixture Species Reference Reproductive problems Aroclors, 1016, 1221, 1242 and 1254 Mink Auerlich, 1977 Fetal death and rcsorption Aroclor 1254 Rabbit Villeneuve, 1971a Reduced litter size Aroclors 1254 and 1260 Rat Linder, 1974 Fetal death and reduced litter weight Aroclor 1254 Rat Spencer, 1982 Cleft palate Kanechlor 500 Mouse Watanabe, 1981 Fetal resorption Aroclor 1254 Rat Baker, 1977 Fetal resorption Clophen A60 Mouse Orberg, 1973 Abortions in chronically fed animals Aroclor 1254 Monkey Arnold, 1990 Reproduction failure Clophen A50 Mink Kihlstrom, 1992 Review of reproductive toxicity from animal Golub, 1991 studies Effects on male fertility Aroclor 1254 Rat Sager, 1991 Delayed First vaginal opening and lower testis Clophen A50 Guinea pig Lundkvist, 1990 weights Decrease in reproductive efficiency Aroclor 1254 Mourning dove Koval, 1987 Decreased reproductive ability and smaller Aroclor 1254 Mouse Linzey, 1988 reproductive organs Decreased weight of seminal vesicles Clophen A60 Mouse Orberg, 1973 Resorptions, abortions and lower birth weights Aroclor 1248 Monkey Barsotti, 1976 Multiple testicular abnormalities Aroclor 1254 Fish Sangalang, 1981 Impaired ovaulation Clophen A30 Monkey Mullcr, 1978 Decreased reproductive success Aroclor 1254 Ring dove McArthur, 1983 Decreased egg hatchabilily Aroclors 1232, 1242, 1248 and 1254 Hen Lillic, 1974 Table 4. cont'd. Response PCB Mixture Species Reference Repressed sex accessory glands Aroclor 1254 Rat Gray, 1992 Inhibition of Bodv Weieht Gain or Bodv Weight Loss Short term feeding (10 d) Aroclor 1254 Rat Spencer, 1982 (14-21 d) Carter, 1983 (14-30 d) Kling, 1978 (2-5 wk) Gartholf, 1977 (6wk) Clophen A50 Baumann, 1983 (6wk) Aroclor 1248 > 1254 > 1260 Alien, 1973 (4wk) Aroclor 1242 Bruckner, 1974b (38 d) Phenoclor DP6, Clophen A60, and Rabbit Vos, 1971 Aroclor 1260 (2-3 mo) Aroclor 1248 Monkey Alien, 1974 Chronic dietary feeding (2y) Aroclor 1254 Rat Morgan, 1981 (21 mo) Aroclor 1260 Kimbrough, 1975 (1 y) Kanechlors 300, 400 and 500 Ito, 1974 (20 wk) Aroclor 1254 Zinkl, 1977 ( - 40 mo) Aroclor 1248 Monkey Barsotti, 1975 (up to 245 d) Aroclor 1242 Becker, 1979 (20 wk) Kanechlor 400 Hori, 1982 (20 wk) Aroclor 1254 Mink Hornshaw, 1986; Auerlich, 1986 Acute, subchronic and chronic studies via various Aroclor 1254 Rat Spencer, 1982; Carter, 1983; routes of exposure Garthoff, 1977; Baumann, 1983; Smialowicz, 1989 Aroclor 1248 Alien, 1973 Aroclor 1242 Bruckner, 19741) Aroclor 1248 Alien, 1975 Monkey Table 4. cont'd. Response PCB Mixture Species Reference Porphyria Elevated urinary coproporphyrins Aroclor 1242 Rat Bruckner, 1974a,b Hepatic porphyrin fluorescence Aroclor 1254 Rat Zinkl, 1977 Increased kidney porphyrins Aroclor 1242 Quail, rats Miranda, 1992 Increased liver and small intestinal porphyrins Aroclor 1242 Quail Miranda, 1987 Increased liver porphyrins and increased ALAS Aroclors 1232, 1248, 1254 and 1260 Rat Grote, 1975a; Schmoldl, 1977 synthesis Increased liver porphyrins Aroclors 1242 and 1016 Rat Goldstein, 1975 Immunotoxicitv Increased mortality to microbial infection Aroclors 1042 and 1016 Mouse Loose, 1978a,b; Thomas, 1978 Decrease formation of splenic PFCs in response Aroclor 1242 Mouse Loose, 1978a to SRBCs Altered graft versus host response Aroclor 1016 Mouse Silkworth, 1978 Reduction in splenic and thymic gamma globulin Aroclor 1254 Rabbit Street, 1975 Reduction in tetanus antitoxin-producing cells Clophen A60 and Aroclor 1260 Guinea pig Vos, 1973 Reduction in gamma globulin producing cells Aroclor 1260 Guinea pig Vos, 1972 Reduction in amibody production to SRBCs Aroclor 1254 Monkey Truelove, 1982 Kanechlor 400 Hori, 1982 Aroclor 1254 Tryphonas, 1989 Modulation of several non-sepcific and specific Aroclor 1254 Monkey Tryphonas, 1991a,b immune parameters Reduction in antibody production to SRBCs Aroclors 1232, 1016, 1242, 1248, 1254 Mouse Davis, 1989; Lubct, 1986 and 1260 Table 4. cont'd. Response PCB Mixture Species Reference Modulation of T-cell function Kanechlor 5(X) Mouse Takagi, 198?' Reduced NK cell activity Aroclor 1254 Rut Smialowic/., 1989, l£xon,1985 Hepatuxicitv Increased liver weight and/or hepatomegaly Several Aroclors Rat Sager, 1983; Carter, 1983; Grant, 1974; Alien, 1979; Garthoff, 1977; Baumann, 1983; Kasza, 1978a,l>; Parkinson, 1983; Hinton, 1978; Kimbrough, 1972, 1975; Jonsson, 1981; Smialowic/., 1989 Phenoclor DP6 Rat Narbonne, 1979 Aroclor 1254 Mouse Sanders, 1974 Phenoclor DP6, Clophen A60 and Mouse Tanimura, 1980 Aroclor 1260 Phenoclor DP6, Clophen A60 and Rabbit Vos, 1971 Aroclor 1260 Aroclors 1221, 1242 and 1254 Rabbit Koller, 1973; Street, 1975 Clophen A60, Aroclor 1260 Guinea pig Vos, 1972, 1973 Kanechlors 300, 400 and 500 Rat Ito, 1974 Aroclor 1248, 1254 Monkey Tryphonas, 1986a,b; Alien, 1974, 1975, 1976 Kanechlors 300, 400 and 500 Mouse Ito, 1973 Aroclors 1221, 1242 and 1254 Mouse Koller, 1977; Kimbrough, 1974 Kanechlor 400 Monkey Hori, 1982 Table 4. cont'd. Response PCB Mixture Species Reference Clophen A50 Mink Kihlstrom, 1992 Diverse indices of fatty liver Clophen A50 Rat Chu, 1977; Baumann, 1983 Aroclors 1242, 1248, 1254, and 1260 Rat Alien, 1973; Jonsson, 1981; Kasza, 1978b; Grant, 1974; Kimbrough, 1972 Aroclor 1248 Monkey Alien, 1974, 1975 Kanechlor 400 Rat Kimura, 1973 Endocrine Effects Increased thyroid activity Aroclor 1254 Rat Bastomsky, 1974 Enlarged thyroid, decreased serum T4 and altered Aroclor 1254 Rat Collins, 1977, 198<)a,b cellular morphology Enlarged thyroid Aroclor 1254 Rat Kasza, 1978a,b Decreased serum progesterone Aroclor 1248 Monkey Barsotti, 1975 Thyroid atrophy Aroclor 1254 Guillemot Jeffries, 1976 Decreased T3 synthesis Aroclors 1254 and 1242 Rat Sepkovic, 1984 Hypothyroidism and decreased serum T3 and/or Aroclor 1254 Rat Byrne, 1987; Mescrvc, 1992; T4 levels Gray, 1992 Increased length of estrus Clophen A60 Mouse Orberg, 1973 Elevated serum corticosterone Aroclor 1254 Mouse Sanders, 1974 No effects on serum hydrocortisone levels Aroclor 1254 Monkey Loo, 1989 Suppression of serum adrenal cortex hormones Aroclors 1254, 1242 and 1016 Rat Byrne, 1988 Low estrogen levels Clophen A30 Monkey Muller, 1978 Table 4. cont'd. Response PCB Mixture Species Reference Multiple steroid and thyroid hormone Aroclor 1254 Ring dove McArthur, 1983 abnormalities Estrogenic activity Aroclor 1221 and other PCB mixtures Rat (iellert, 1978; Ecobichon, 1974 Neurotoxicitv Developmental neurotoxicity (review) Tilson, 1990 Neurobehavioral toxicity (review) Monkey SchanU, 1991 Decreased brain catecholamines Aroclors 1254 and 1260 Rat Seegdl, 1986a,b Increased locomotcr activity and retarded learning Aroclor 1248 Monkey Bowman, 1978, 1981 activity Delayed spatial alternation deficits Aroclor 1248 Monkey Levin, 1988 Decreased brain calecholamine levels Aroclors 1016 and 1260 Macaque Seegal, 1991 C'entral nervous system loxiuly Aroclor 1254 Mouse Albrecht, 1987 Increased behavioral toxicity due to prenatal Clophen A30 Rat Lilienthul, 1990, 1991 exposure Fenclor 42 Rat Pantaleoni, 1988 Imparted discrimination reversal learning Aroclor 1248 Monkey Schant/, 1989 Altered serotonin levels in the brain Aroclors 1254 and 1260 Rat Seegal, 1986a Impaired neurobehavioral activity after perinatal Aroclor 1254 Rat Overmann, 1987 exposure Thvmic Atrophy and Thymus Toxicity Thymic atrophy and ihymus toxicity Clophen A60 and Aroclor 1260 Guinea pig Vos, 1973 Table 4. cont'd. Response PCB Mixture Species Reference Aroclor 1254 Yorkshire pig Miniats, 1978 Aroclor 1254 Rat Smialowicz, 1989 Dermal Toxicity Alopecia, edema, distinctive hair follicles and hair Aroclor 1248 Monkey Alien, 1974b, 1975; Barsolli, loss 1975, 1976 Hyperkeratosis and other lesions on the ear Aroclor 1254 Rat Zinkl, 1977 Hair loss and other skin lesions Aroclor 1254 Monkey Becker, 1979 Lost fingernails Aroclor 1254 Monkey Truelove, 1982 Meibomian cysts, skin hyperkeratosis Kanechlor 400 Monkey Hori, 1982 Fingernail loss and exuberant nail beds Aroclor 1254 Monkey Tryphonas, 1986a,b Carcinogenicity Neoplastic nodules, hepatocellular carcinoma Aroclor 1254 Rat Kimbrough, 1975 Aroclor 1260 Norback, 1985 Neoplastic nodules, hepatocellular carcinoma, Aroclor 1254 Rat Morgan, 1981; NCI, 1978; Ward, gastric adenocarcinoma and intestinal metaplasia 1985 Adenofibrosis, neoplastic nodules Aroclor 1260 Rat Rao, 1988 Neoplastic nodules Clophen A30 Rat Schaeffer, 1984 Kanechlor 400 Kimura, 1973 Neoplastic nodules, hepatocellular carcinoma Clophen A60 Rat Schaeffer, 1984 and/or adenof brosis Kanechlor 400 Ito, 1974 Neoplastic nodules, hepatocellular carcinoma Kanechlor 500 Mouse Ito, 1973 Table 5. PCB mixtures as promoters: formation of tumors or preneoplastic lesions. Response PCB Mixture Species Carcinogen Reference Increased incidence of Aroclor 1254 S-D rats diethylnitrosamine Preston, 1981 hepatocellular carcinoma Kanechlor 400 Donryu rats 3'-methyl-4-dimethyl- aminoazo- Kimura, 1976 benzene Kanechlor 500 Wistar rats diethylnitrosamine Nishizumi, 1976 Kanechlor 500 dd mice 0-hexachlorocyclohexane isomers Ito, 1973 Increased formation of Kanechlor 500 F344 rats 2-acetylaminofluorene Tatematsu, 1979 neoplastic nodules (liver) Increased incidence of skin Aroclor 1254 HRS/J hairless mice AT-methyl-/v'-nitrosoguanidine Poland, 1982b tumors Increased incidence of putative Aroclor 1254 S-D rats diethylnitrosamine Periera, 1982 hepatic preneoplastic lesions Phenoclor DP6 S-D rats aflatoxin Bl Pelissier, 1992 Clophen A30 + A50 S-D rats diethylnitrosamine Oslerle, 1983, 1984 Deml, 1982 Clophen A50 S-D rats benzo[a]pyrene Deml, 1983 Clophen C Chickens diethylnitrosamine Brunn, 1987 Increased incidence of lung Aroclor 1254 Swiss mice jV-nitrosodielhylamine Beebe, 1991; Andersson, tumors 1983, 1991 Table 6. PCB mixture-induced biochemical effects. Responses PCB Mixture Species Reference induction of P450-Dependent Enzvmes or Isozvmes Induction of O- and N-dealkylase activity Aroclors 1248, 1254 and 1260 Rat Alien, 1973 Aroclors 1016, 1221, 1232, 1242, 1248, Ecobichon, 1975 1254 and 1260 Aroclor 1242 Bruckner, 1974b Clophen A50 Parkki, 1977 Aroclors 1248, 1254 and 1262 Alien, 1979 Aroclor 1254 Beebe, 1991 Induced P450 levels Aroclor 1254 Rat Alvares, 1979; Hinton, 1978 Clophen A50 Parkki, 1977 Guinea pig Brunstrom, 1982 Decreased barbituate sleeping times Aroclor 1254 Mouse Sanders, 1974 Induction of diverse hydroxylases Aroclors 1016, 1221, 1232, 1242, 1248, Rat Ecobichon, 1975 1254 and 1260 Aroclor 1242 Bruckner, 1974b Induction of AHH activity Clophen A50 Rat Parkki, 1977 Mink Brunstrom, 1991 Aroclor 1242 Quail Miranda, 1992 Aroclors 1016, 1232, 1242, 1248, 1254 Rat Harris, 1993 and 1260 Aroclor 1254 Lubet, 1991 Other Biochemical Responses Increased ALA synthetase Aroclor 1254 Rat Alvares, 1979 Aroclor 1242 Quail Miranda, 1992 Table 6. cont'd. Responses PCB Mixture Species Reference Decreased ALA dehydratase Aroclor 1254 Rat Alvares, 1979 Increased epoxide hydrolase Clophen A50 Rat Parkki, 1977 Aroclor 1254 Lubet, 1991 Increased glucuronosyl transferase Clophen A50 Rat Parkki, 1977 Induction of c-Ha-ras, c-raf, c-yes, c-erbA and c- Clophen A50 Rat Jenke, 1991 erbB protooncogene mRNA levels Increased serum lipids and HMG CoA reductase Clophen A50 Rat Jenke, 1985, 1988 Increased indices of hepatic lipoperoxidation Rat Dogra, 1988; Kamohara, 1984; Pelissier, 1992 Hypocholesterolem ia Aroclor 1248 Rat Nagaoka, 1990 Increased fatty acid desaturation Aroclor 1254 Rat, pigeon Borlakoglu, 1990a Modulation of plasma lipoproteins Aroclor 1254 Chick Griffin, 1991 Induction of lung pepsinogen isozymes Kanechlor 400 Hamster Imaida, 1991 Decreased uioporphyrinogen decarboxylase Aroclor 1242 Quail Miranda, 1992 Aroclor 1254 Rat Smith, 1990 Increased aldehyde hydrogenase Aroclor 1254 Rat Lubet, 1991 Inhibition of citrate cleavage enzyme Aroclor 1254 Rat Kling, 1981 Binding to the cytosolic Ah receptor Aroclor 1254 Rat Bandiera, 1982 Others Increased serum cholesterol and lipids Clophen A50 Rat Baumann, 1983 Aroclors 1248, 1254 and 1262 Alien, 1976 Increased serum SGPT, SCOT Clophen A50 Rat Baumann, 1983 Decreased hepatic vitamin A Clophen A50 Mink Brunstrom, 1991, 1992b Table 7. Biochemical and toxic responses elicited by the coplanar PCBs, 3,3',4,4'-tetraCB, 3;3',4,4',5-pentaCB and 3,3',4,4',5,5'- hexaCB. Response 3,3',4,4'-TetraCB 3,3',4,4',5-PentaCB 3,3',4,4',5,5'-HexaCB Induction of CYPlAl and CYP1A2 Goldstein, 1977 Yoshimura, 1978, 1979 Goldstein, 1977b, 1981, 1982 gene expression and associated Yoshimura, 1978, 1979 Ozawa, 1979a, 1979b Yoshimura, 1978, 1979 monooxygenasc enzyme activities Poland, 1977 Parkinson, 1980, 1983 Poland, 1977 Parkinson, 1980, 1983 Yoshihara, 1979, 1982, 1983 James, 1981 Sawyer, 1982 Sawyer, 1982 Parkinson, 1980, 1983 Brunstrom, 1986 Rodman, 1989 Sawyer, 1982 Rodman, 1989 EHiott, 1991 Kohli, 1980, 1981b Gooch, 1989 Nagata, 1985 Miranda, 1990 Monosson, 1991 Tillitt, 1991 Rodman, 1989 Stegeman, 1991 Sinclair, 1990 Hardwick, 1985 Tillitt, 1991 Leece, 1985 Luster, 1983 Janz, 1991 Brunstrom, 1991 Sundheimer, 1983 Gillette, 1987 Van Birgelen, 1992 Tillitt, 1991 Sinclair, 1990 De Vito, 1993 Brunstrom, 1990 Leece, 1985 Sinclair, 1990 Nikolaidis, 1988 Leece, 1985 Brunstrom, 1991 Brunstrom, 1991 De Vito, 1993 De Vito, 1993 Suppression of constitutive Yeowell, 1987, 1989 CYP2C11 gene expression Induction of CYP4A1-dependent Borlakoglu, 1992 Huang, 1991 activities Induction of glutathione S- Aoki, 1992 Kohli, 1979 tranferases Aoki, 1992 Induction of epoxide hydrolase Ahotupa, 1981 Binding to the rat cytosolic Ah Bandiera, 1982 Bandiera, 1982 Bandiera, 1982 receptor Table 7. cont'd. Response 3,3',4,4'-TetraCB 3,3',4,4',5-PentaCB S.S'^'.S.S'-HexaCB Inhibition of uroporphyrinogen Lambrecht, 1990 Kawanishi, 1981, 1983 ciecarboxylasc activity Sinclair, 1984, 1986 Kawanishi, 1981, 1983 Swain, 1983 Induction of ALAS activity Kawanishi, 1983 Kawanishi, 1983 Hypothyroidism and decreased Spear, 1985 serum thyroid hormone levels Van den Berg, 1988 Decreased hepatic or plasma Chen, 1992a Chen, 1992a vitamin A levels Brower, 1984, 1985, 1988 Azais, 1986, 1987 Narbonne, 1990 Spear, 1986 Powers, 1987 Thymic atrophy and toxicity to Yoshimura, 1979 Yoshimura, 1979 Biocca, 1981 thyrnic cells Leece, 1985 Leece, 1985 Yoshimura, 1979 Nikolaidis, 1988a,b Andersson, 1991 Leece, 1985 Andersson, 1991 McKinney, 1976 Andersson, 1991 Kohli, 1979, 1981 Hepatotoxicity, including Yoshimura, 1979 Yoshimura, 1979 Biocca, 1981 hepatomegaly, fatty liver Kohli, 1979a, 198 la Yoshimura, 1979 Reproductive and/or Spear, 1989 Mayura, 1993 Marks, 1981 ' developmental toxicity Brunstrom, 1983, 1991 Brunslrom, 1990a,b, 1991 Brunstrom, 1991 Marks, 1989 Ncurobehavioural and neurotoxic Tilson, 1979 responses Eriksson, 1988, 1991 Chou, 1979 Dermal toxicity McNulty, 1980 Table 7. cont'd. Response 3,31,4,4'-TetraCB 3,3',4,4',5-PentaCB 3,3',4,4',5,5'-Hex;i('B Body weight loss Lccce, 1985 Leecc, 1985 Lecce, 1985 Biocca, 1981 Porphyria (accumulation of octa- Miranda, 1987 Sinclair, 1990 Goldstein, 1976 and heptacarboxyporphyrins) Sinclair, 1986, 1990 Biocca, 1981 Sassa, 1986 Sinclair, 1986, 1990 Kawanishi, 1981 Sassa, 1986 Kawanishi, 1981 Immunosupprcssive activities Silkworth, 1982, 1984 Mayura, 1993 Kerkvliet, 1988a, 1988b Mayura, 1993 Mayura, 1993 Clark 1983 Tumor promoter activity Buchmann, 1986, 1991 Flodstrom, 1992 Sargent, 1991, 1992 Luebeck, 1991 Embryolethality (fish) Walker, 1991 Walker, 1991 Table 8. Biochemical and toxic responses elicited by the monoortho coplanar PCBs. Response Congener (Reference) Induction of CYP1A1 and CYP1A2 gene 2',3,4,4',5-pentaCB (Parkinson, 1980b, 1983; Sawyer, 1982; Leece, 1985; expression and associated monooxygenase Robertson, 1984) activities 2,3,4,4',5-pentaCB (Parkinson, 1980b, 1982, 1983; Rodman, 1989; Sawyer, 1982) 2,3,3',4)4'-pentaCB (Parkinson, 1980b, 1983; Sawyer, 1982; Yoshimura, 1979; Robertson, 1984; Flodstrom, 1992; Leece, 1985; De Vito, 1993) 2,3',4,4',5-pentaCB (Parkinson, 1980b, 1983; Sawyer, 1982; Skaare, 1991; Robertson, 1984; Leece, 1985) 2,3,3',4,4',5-hexaCB (Parkinson, 1980b, 1983; Sawyer, 1982, Robertson, 1984; Van Bergelen, 1992; Leece, 1985; De Vito, 1993) 2,3',4,4'(5,5'-hexaCB (Parkinson, 1980b, 1983; Sawyer, 1982; De Vito, 1993) 2,3,3',4,4',5'-hexaCB (Parkinson, 1980b, 1983; Rodman, 1989; Sawyer, 1982; Robertson, 1984; Leece, 1985) 2,3,3',4,4')5,5'-heptaCB(Parkson) 1980a,b, 1983; Sawyer, 1982; Corbett, 1982; Robertson, 1984) Induction of epoxide hydrolase All eight congeners noted above (Parkinson, 1983) Inhibition of body weight gain 2,3,3',4,4'-pentaCB (Yamamoto, 1976; Leece, 1985) 2,3',4,4',5-pentaCB (Leece, 1985) 2',3,4,4',5-pentaCB (Leece, 1985) 2,3,3',4,4',5-hexaCB (Leece, 1985) 2,3,3',4,4',5'-hexaCB (Leece, 1985) Table 8. cont'd. Response Congener (Reference) Immunosuppressive effects 2,3,3 ,4,4',5-hexaCB (Silkworth, 1984; Davis, 1990) Thymic atrophy 2,3,3',4,4'-pentaCB (Parkinson, 1983; Robertson, 1984; Andersson, 1991; Leece, 1985) 2,3,3',4,4',5-hexaCB (Leece, 1985; Robertson, 1984; Andersson, 1991; Parkinson, 1985) 2,3,3',4,4')5'-hexaCB (Parkinson, 1983; Leece, 1985) 2,3,4,4',5-pentaCB (Leece, 1985) Hepatoxicity including hepatomegaly, fatty W^'-pentaCB (Yamamoto, 1976; Yoshimura, 1979) liver Tumor promoter activity 2,3,3',4,4'-pentaCB (Flodstrom, 1992) 2,3,4,4',5-pentaCB (Buchman, 1991) Reproductive and developmental toxicity 2,3',4,4',5-pentaCB (Ax, 1975; Walker, 1991) including embryolethality (fish) 2,3,3',4,4'-pentaCB (Walker, 1991; Brunstrom, 1990) 2,3,3',4,4',5-hexaCB (Brunstrom, 1990; Birnbaum, 1987) 2,3,3',4,4')5'-hexaCB (Brunstrom, 1990) Antiestrogenicity in MCF-7 human breast 2,3,3',4,4',5-hexaCB, 2,3,3',4,4'-pentaCB, 2,3,4,4',5-pentaCB (Krishnan, 1993) cancer cells Table 9. PCBs: summary of structure-induction/binding relationships (from Safe, 1985a). Cytochromes P450 Induction Relative Activity (% of control)1 P450c P450b AHH Induction (%) Receptor Binding" PCB Structures P450d P450e In Vivo* In Vitro" Coplanar PCBsc (3) 4100 - 1800 No induction + + + 100-1 100 - 35 Mono-ort/io coplanars (8) 2400 - 750 4700 - 2600 + + 0.3 - 2.4 x 105 6- 1.5 Di-orf/io coplanars (12) 900 - 250 6300 - 1000 + Inactive < 0.3' 2,2',4,4',5,5'-Hexa- No induction 7300 Inactive Inactive < 0.3' chlorobiphenyl 2,3,7,8-TCDD 3500 No induction + + + + + 400 2500 Male Long-Evans rats (dose: 500 /xmol/kg). Male Wistar rats (dose: 300 /xmol/kg). Rat hepatoma H-4-II E cells. Determined by the competitive displacement of [3H]TCDD bound to male Wistar rat hepatic cytosol. 3,3',4,4'-Tetra, 3,3',4,4',5-penta- and 3,3',4,',5,5'-hexachlorobiphenyl. Represents nonspecific binding. 114 Table 10. Effects of commercial Aroclors, TCDD and commercial Aroclors plus TCDD on the PFC response to SRBCs in C57BL/6 mice (Davis, 1989). Treatment (dose) Plaque-forming Cells/ Plaque-forming Cells/ Spleen (x 105) 106 Viable Cells Control (corn oil)* 1.12 ± 0.17 912 ± 221 TCDD (1.2 Mg) 0.30 ± 0.08 180 ± 35 Aroclor 1232 (25 mg/kg) 1.09 ± 0.10 960 ± 126 Aroclor 1232 (25 mg/kg) 0.34 ± 0.10 244 ± 63 + TCDD (1.2 Mg) Aroclor 1242 (25 mg/kg) 0.94 ± 0.15 725 ± 75 Aroclor 1242 (25 mg/kg + 0.49 ± 0.04b 440 ± 96" TCDD (1.2 Mg) Aroclor 1248 (25 mg/kg) 1.04 + 0.01 741 ± 191 Aroclor 1248 (25 mg/kg) 0.54 ± 0.14' 427 ± 110b + TCDD ( 1.2 Mg) Aroclor 1254 (25 mg/kg) 1.02 ± 0.07 802 ± 84 Aroclor 1254 (25 mg/kg) 0.63 ± 0.05" 459 ± 86b + TCDD (1.2 Mg) Aroclor 1260 (25 mg/kg) 0.95 ± 0.14 756 ± 112 Aroclor 1260 (25 mg/kg) 0.71 ± 0.28" 459 ± 93b + TCDD (1.2 /xg) Control group contained 9 animals; all other groups contained 4 animals; the treatments did not affect the spleen cell viability. Significantly different (p < 0.05) from animals treated with TCDD alone. Significantly different (p < 0.01) from animals treated with TCDD alone. 115 Table 11. Aroclor 1254 as a 2,3,7,8-TCDD antagonist in C57BL/6 mice - summary (Davis. 1989; Haake, 1987; Bannister, 1987). % Maximum Antagonist/Agonist Window Response Antagonism AHH induction 20 1,667- 10,000/1 EROD induction 23 1,667 - 10,000/1 Thymic atrophy 0 No antagonism observed Immunotoxocity 100 1,340 - 20,160/1 Teratogenicity 80 ± 12,100/1 116 the splenic PFC response in C57BL/6J mice treated with SRBCs (Biegel, 1989). Treatment Spleen Cellularity PFCs/spleen PFCs/106 Viable % of (dose, jimol/kg) (x 107) (xlO5) Spleen Cells Control Corn oil 12.6 ± 3.4 1.36 ± 0.14 1127 ± 213 ' 100 TCDD (0.0037) 13.3 ± 2.4 0.37 ± 0.06 284 ± 48 25 HexaCB (100) 15.1 ± 3.7 1.46 ± 0.17 995 ± 88 HexaCB (400) 17.6 ± 1.9 1.56 ± 0.08 979 ± 192 87 HexaCB (1000) 13.1 ± 2.7 1.42 ± 0.07 1117 ± 277 99 HexaCB (100) + 15.4 ± 3.7 0.37 ± 0.08 244 ± 60 22 TCDD (0.0037) HexaCB (400) + 123 ± 2.7 1.14 ± 0.04 936 ± 144 83 TCDD (0.0037) HexaCB (1000) + 13.8 ± 1.7 1.36 ± 0.08 995 ± 93 88 TCDD (0.0037) 117 Table 13. Proposed TEFs for the 2,3,7,8-substituted PCDDs and PCDFs (Safe. 1990). Relative Potency Ranges In Vivo In Vitro Congener Toxicities Toxicities TEF A. PCDDs 2,3,7,8-TCDD 1.0 1,2,3,7,8-PentaCDD 0.59 - 0.053 0.64 - 0.07 0.5 1,23,4,7,8-HexaCDD 0.24 - 0.013 0.13 - 0.05 0.1 1,2,3,6,7,8-HexaCDD 0.16 - 0.0152 0.5 - 0.005 0.1 1,2,3,7,8,9-HexaCDD 0.14 - 0.016 0.009 0.1 1,2,3,4,6,7,8-HeptaCDD 0.0076 0.003 0.01 OCDD > 0.0013 0.0006 0.001 B. PCDFs 2,3,7,8-TCDF 0.17 - 0.016 0.43 - 0.006 0.1 2,3,4,7,8-PentaCDF 0.8 - 0.12 0.67 - 0.11 0.5 1,2,3,7,8-PentaCDF 0.9 - 0.018 0.13 - 0.003 0.1/0.05 1,2,3,4,7,8-HexaCDF 0.18 - 0.038 0.2 - 0.013 0.1 2,3,4,6,7,8-HexaCDF 0.097 - 0.017 0.1 - 0.015 0.1 1,2,3,6,7,8-HexaCDF 0.048 - 0.037 0.1 1,2,3,7,8,9-HexaCDF 0.1 1,2,3,4,6,7,8-HeptaCDF 0.22 0.1V0.010 1,2,3,4,7,8,9-HeptaCDF 0.20 0.1V0.01b OCDF 0.001 Recommended by Safe, 1990. Currently used TEFs (NATO/CCMS, 1988). Table 14. Comparative toxic and biochemical potencies of 3,3',4,4'-tetraCB, 3,3',4,4',5-pentaCB and 3,3',4,4',5,5'-hexaCB. EDM or ECy, Values fog/kg- or fig/L") Response (ref.) Species 3,3',4,4'-TetraCB 3,3',4,4',5-PentaCB 3,3',4,4',5,5'-HexaCB TCDD Body weight loss1 (Leece, 1985) Rat (W) > 1.46 x 10s 1.08 x 103 5.41 x 103 16.1 Thymic atrophy* (Leece, 1985) Rat (W) > 1.46 x 10s 3.10 x 102 3.21 x 103 29.0 Hepatic EROD induction* Rat (W) > 1.46 x 10s 39.2 236 0.97 (Leece, 1985) Hepatic AHH induction* (Leece, Rat (W) ~ 1.46 x 105 359 181 1.29 1985) Cytosolic Ah receptor binding6 Rat (W) 12.6 x 104 3.9 x 104 insoluble 3.2 x 10' (Bandiera, 1982) Immunotoxicity* (Mayura, 1993) Mouse (C57BL/6) 5.7 1.7 0.7 0.77 (Mayura, 1993) Mouse (C57BL/6) 28.2 1.0 2.7 0.77 (Harper, 1993) Mouse (C57BL/6) 8.0 15 1.4 (Harper, 1993) Mouse (C57BL/6) 12 20 1.5 (Harper, 1993) Mouse (DBA/2) 69 69 11.2 (Harper, 1993) Mouse (DBA/2) 72 71 9.7 LDjo* (Brunstrom, 1990a,b) Chick embryo 8.46 3.07 173 Hepatic EROD induction* Chick embryo 1.75 0.097 14.4 (Brunstrom, 1990a,b) Hepatic EROD induction" (Yao, Chick embryo 0.67 0.39 - - - 0.025 1990) hepalocytes Hepatic AHH induction" (Yao, Chick embryo 0.35 0.41 _ . _ 0.007 1990) hepatocytes 3 AHH induction (Sawyer, 1982) H4I1-E cells 10.2 0.078 21.8 0.031 EROD induction" (Sawyer, H4I1-E cells 25.8 0.081 8.70 0.026 1982) Table 14. cont'd. a b EDM or ECW Values (/*g/kg or ^g/L ) Response fref.) Species 3,3',4,4'-TetraCB 3,3',4,4',5-PentuCB 3,3',4,4',5,5'-HexaCB TCDD Inhibition of lymphoid Chick embryo 14.6 1.31 108.3 development* (Brunsfrom, I990a,b) Early life stage mortality LDg, Rainbow 1348 x 103 74 x 103 240 values (vValker, 1991) trout (ER) Inhibition of bursal lymphoid Chick embryo 50 4 300 development (Andersson, 1991) Inhibition of lymphoid Fetal mouse 58.4 - 87.6 0.65 72.1 - 108 0.064 development in mouse-thymi (C57BL/6) (Andersson, 1991) 1 eratogenicity (Mayura, 1993; 261 - 522 < 20 Haake, 1987) Table 15. Response-specific TEF values for 3,3',4,4',5-pentaCB, 3,3',4,4'-tetraCB and 3,3',4,4',5,5'-hexaCB. Response 3,3',4,4',5-PentaCB 3,3',4,4'-TctraCB S.S'^'.S.S'-HexaCB Rat: 14-day study (Ifece, 1985) body weight loss, thymic atrophy, AHH and 0.015, 0.093, 0.07, 0.025 1 x lO^1, 2 x 10", 3 x 10 \ 9 x 103, EROD induction 9 x lO"6, 7 x 10* 7 x 10J, 4 x 103 Rat: 3-month study (Van Birgelen, 1992) several responses in which LOELs and 0.06 - 0.6 not available not available NOELs were compared Mouse: immunotoxicity and teratogenicity (Mayur.-i, 1993; Harper, 1993) inhibition of the SRBC-induced response 0.45, 0.77 0.13, 0.03 1.1, 0.29 inhibition of the TNP-LPS-induced response 0.09, 0.08, 0.16, 0.14 not available 0.09, 0.05, 0.16, 0.14 teratogenicity (est.) 0.07 - 0.04 not available not available inhibition of thymus lymphoid development 0.098 1.1 x 103 - 7.3 x 10" 8.9 x 10" - 5.9 x 10" Chick embryos (Brunstrom, IWOa.b; Yao, 1990; Bosveld, 1992) AHH induction 0.017 0.02 EROD induction 0.06, 0.1 0.037, 0.02 <, 0.10 x 11 Rat hepatoma H4II-E cells (Sawyer, 1992) AHH induction 0.40 3.0 x 10 3 1.4 x 10 J EROD induction 0.32 1.0 x 10 3 3.0 x 10 3 Table 15. cont'd. Response 3,3',4,4',5-PentaCB 3,3',4(4'-TetraCB 313',4)4',5,5'-HexaCB Rainbow trout (Walker, 1991) early life-stage mortality 0.003 1.8 x not available Tumor-promoting activity (Flodstrom, 1992) (est.) 0.1 not available not available Table 16. Biochemical and toxic potencies for the monoortho coplanar PCBs and their derived TEF values. Response (ref.) ,,, Values (1EF) (mg/kg or mg/L1) Induction of AHH and EROD activity in rats (Lccce, 1985) 2,3,4,4',5-pentaCB, 9.8 (1.3 x 10^: 19.6 (IP_xJO_!) 2,3,3',4,4',5'-hexaCB, 2.16 (6.0 x 10^: 2.53 (3.8 x 10^ 2,3,3',4,4',5-hexaCB, 2.53 (5.1 x 10^: 9.0 (1.1 x 10^) 2,3,3',4,4'-pentaCB, 21.2 (6JjOP_!) 2,3',4,4',5-pentaCB, 53.8 (2.4 x 1Q\ 83.3 (1.2 x 10s) 2',3,4,4',5-pentaCB, 42.4 (3.0 x 10*): 71.1 (1.4 x 105) Body weight loss and thymic atrophy in rats (Leece, 1985) 2,3,4,4',5-pentaCB, 58.7 (2.7 x 10^: 65.3 (4.4 x 10^1 2,3,3',4,4',5'-hexaCB, 79.4 (2.0 x Iff*); 81.2 (3.6 x 10^ 2,3,3',4,4',5-hexaCB, 65.0 (2.5 x 10"): 65.0 (2.5 x 10") 2,3,3',4,4'-pentaCB, 245 (6.6 x 105): 336 (8.6 x 105) 2,3',4,4',5-pentaCB, 366 (4A x 10s): 506 (5.7 x 105) 2',3,4,4',5-pentaCB, 121 (1.3 x 10"): 911 (12_xJO_!) Immunotoxicity in C57BL/6 mice (Davis, 1990) 2,3,3',4,4',5-hexaCB, 0.72 (1.1 x 103) Lethality (LDjg) in chick embryos (Brunstrom, 1990) 2,3,3',4,4'-pentaCB, 2.19 (3.8 x 10")* 2,3,3',4,4',5'-hexaCB, 2.49 (3.4 x 10")* 2,3,3',4,4',5-hexaCB, 1.52 (5.6 x 10")* 2,3',4,4',5-pentaCB, > 4.01 (2.1 x 10V Hepatic EROD induction in chick embryo (Brunstrom, 1990) 2,3,3',4,4'-pentaCB, 0.15 (1.2 x 10'V 2,3',3,4,4',5-hexaCB, 0.20 (8.8 x 10")* 2,3,3',4,4',5-hexaCB, 0.14 (1.3 x 10 V 2,3',4,4',5-pentaCB, 2.19 (8.9 x 105)* Hepatic AHH and EROD induction in chick embryo hepatocytes (Yao, 1990)* 2,3,3',4,4'-pentaCB, 0.13 (5.4 x 10s): 0.030 (8.3 x 10") 2,3',4,4',5-pentaCB, 0.030 (2.3 x IQ^i: 0.098 (2.6 x 10^^ 2,3,3',4,4',5-hexaCB, 0.54 (1.3 x 10\ 0.51 (4.9 x 10s) Hepatic AHH and EROD induction in rat hepatoma H4II-E cells (Sawyer, 1982)' 2,3,3',4,4'-pentaCB, 0.029 (1.1 x U)Jk 0.039 (6.7 x 10') 2,3',4,4',5-pentaCB, 3.75 (8_xJP_?); 2.89 (8.9 x 10^ 2,3,4,4',5-pentaCB, 0.32 (9.8 x Iff1): 0.184 (1.4 x 10^) 2',3,4,4',5-pentaCB, 1.28 (2.4 x 10si: 0.362 (7.2 x 105) 2,3,3,',4,4',5-hexaCB, 0.74 (4,1 x 10s): 0.32 (SJjOOj) 2,3,3',4,4',5-hexaCB, 0.46 (6 x 105V. 0.26 (10^) Table 16. cont'd. Response (ref.) *, Values (TER fmg/kg or mg/L1) Eiarly lift stage mortality LD,,, values in rainbow trout (Walker, 1991)* 2,3,3',4,4'-pentaCB, > 6970 (< 3.4 x 10s) 2,3',4,4',5-pentaCB, > 6970 (< 3.4 x 10s) Inhibition of lymphoid development in the fetal mouse (Andersson, 1991) 2,3,3',4,4',5-hexaCB, (< 9.8 x 10s) Tcratogenicity in C57BL/6N mice (Birnbaum, 1987) 2,3,3',4,4',5-hexaCB, 118.5 (3_xJ Derived from the ratio ED50(3,3',4,4',5-pentaCB)/ED50(congener) x 0.1. 124 Table 17. Proposed TEFs for coplanar and selected monoortho coplanar PCBs. Relative Potency Range Mean TEF Congener (in vivo and in vitro) ( ± SD) (n)1 Proposed TEF 3,3',4,4',5-PentaCB 0.003 - 0.77 0.19 ± 0.22 (21) 0.1 3,3',4,4',5,5'-HexaCB 0.00059 - 1.1 0.053 ± 0.089 (13) 0.05 3.3',4,4'-TetraCB 0.000007 - 0.13 0.017 ± 0.030 (19) 0.02 2,3,3',4,4'-PentaCB 0.000034 - 0.0012 0.00098 ± 0.002 (10) 0.001 2,33',4,4',5-HexaCB 0.0011 - 0.000013 0.00048 ± 0.00043 (14) 0.0003 23', 4.4' ,5 PentaCB 0.0000089 - 0.00026 0.000088 ± 0.0000% (11) 0.0001 2,3,3',4,4',5'-HexaCB 0.0006 - 0.00006 0.00029 ± 0.00019 (7) 0.0003 2',3,4,4',5-PentaCB 0.00013 - 0.000014 0.00005 ± 0.000044 (6) 0.00005 2,3,4,4' ,5-PentaCB 0.00044 - 0.00005 0.00019 ± 0.00014 (6) 0.0002 • Number of responses. 125 Table 18. 2,3,7,8-TCDD equivalents in human adipose tissue samples from the PCDDs, PCDFs and coplanar PCBs (Tanabe, 1989). 2,3,7,8-TCDD TEF Concentration Equivalents Congener (TEF)* (PPt) (PPt) 2,3,7,8-TCDD 1.0 3.7 3.7 1,2,3,7 8-PentaCDD 0.5 6.4 3.2 1,2,3,4,7,8-HexaCDD 0.1 3.9 0.39 1,2,3,6,7,8-HexaCDD 0.1 34 3.4 1,2,3,7,8,9-HexaCDD 0.1 5.7 0.57 1,2,3,4,6,7,8-FeptaCDD 0.01 33 0.33 OCDD 0.001 510 0.51 Total 12.01 2,3,7,8-TCDF 0.1 3.1 0.31 1,2,3,7,8-PentaCDF 0.1 0.5 0.05 2,3,4,7,8-PentaCDF 0.5 11.0 6.5 1,2,3,4,7,8-HexaCDF 0.1 5.6 0.56 2,3,4,6,7,8-HexaCDF 0.1 1.4 0.14 1,2,3,6,7,8-HexaCDF 0.1 5.3 0.53 1,2,3,7,8,9-HexaCDF 0.1 0.029 1,2,3,4,6,7,8-HeptaCDF 0.01 2.9 0.029 1,2,3,4,7,8,9-HeptaCDF 0.01 ... - . . OCDF 0.001 ...... Total 8.12 3,3',4,4',5-PentaCB 0.1 (0.1) 330 33.0 (33.0) 3.3',4,4',5,5'-HexaCB 0.05 (0.05) 90 4.5 (4.5) 3,3',4,4'-TetraCB 0.10 (0.02) 350 3.5 (7.0; Total 41.0 (44.5) Revised TEFs as summarized in Table 17. 126 Table 19. Concentrations of coplanar and monoortho coplanar PCBs in Aroclors 1016, 1242, 1254 and 1260 (Schulz. 1989'; Kannan, 1988bb). Concentration (Mg/g) Congener Substitution 1016 1242 1254 1260 3,3',4,4',5- 17 46 8.3 3,3',4,4',5,5'- 0.05 0.5 0.05 3.3',4,4'- 5,200 600 260 2,3',4,4',5- 16,200 63,900 5,700 2,3,3',4,4'- 8,600 38,300 700 2,3',4,4',5,5'- ...... 2,100 2,600 2,3,3',4,4',5- 900 16,200 8,800 2,3,3',4,4',5'- ...... 1,400 2',3,4,4',5- ...... 8,100 2.3,3'.4.4'.5.5'- 1,100 Total Concentrations of monoorthocoplanar PCBs. Concentrations of coplanar PCBs. 127 Table 20. Application of the TEF approach for calculating the immunotoxicity of Aroclors 1016, 1242, 1254 and 1260 in C57BL/6 mice: comparison of observed (Davis, 1989) versus calculated ED50 values. Aroclors Parameter 1016 1242 1254 1260 TEQs (Mg/g (calculated) (4 congeners only)' - 0 696 146.6 52.6 ED;,, (mg/kg) (calculated from the TEQs and - 0 1.1 5.25 14.6 utilizing ED-., (TCDD) = 0.77 /ig/kg) ED,,, (mg/kg) (observed) 464 400 118 104 EDjo (observed) / ED*, (calculated) or 364 22.5 7.1 3,3'<4,4'-TetraCB,3,3',4,4',5-pentaCB,3,3',4>4',54'-hexaCB,2,33',4,4',5-hexaCB;concentrationsofindividuaJ congeners shown in Table 19 and the TEF values were derived from Davis (1990) and Mayura (1993). 128 Table 21. Application and validation of the TEF approach for predicting the induction activities of Aroclors 1242, 1254 and 1260 in male Wistar rats (Hams. 1993). Aroclors Parameter 1242 1254 1260 TEQs (Mg/g) AHH induction-derived 1.41 12.35 5.45 EROD induction-derived 2.24 9.95 2.43 ED,,, (rug/kg) (calculated from TEQs and utilizing EDM(TCDD)) AHH induction (EDM(TCDD) = 1.29 /zg/kg) 915 104 422 EROD induction (EDsjCTCDD) = 0.97 ^tg/kg) 433 102 251 £0,0 (mg/kg) observed AHH induction 84 92 343 EROD induction 346 137 442 EDJO(observed)/ED50(calculated) AHH induction 0.09 0.88 0.812 EROD induction 0.80 1.34 1.76 129 Table 22. Limitations of the TEF approach for PCB-induced carcinogenicity in female Sprague- Dawley rats (Kociba, 1978; Norback, 1985). Adenocarcinomas Concentration TEQ Treatment in feed (ppO Male . Female Control (corn oil) 0 0 TCDD 210 ppt 210 0 2/50 (4%) TCDD 2100 ppt 2100 0 11/50 (22%) Aroclor 1260 100 ppm 1040* 0 24/47 (51%) The TEQ of 10.4 ppm was calculated from the concentrations given in Table 19 and the TEFs in Table 17. 130 FIGURE CAPTIONS Figure 1. PCB congeners which persist in human tissues. Figure 2. Structures of coplanar PCB congeners and 2,3,7,8-TCDD. Figure 3. Structures of monoortho coplanar PCBs. Figure 4. Scheme for the metabolism of PCBs. Figure 5. Examples of PCBs and metabolites which elicit Ah receptor-independent responses. l 1 1 1 l 2,2',3',4,4',5-hexaCB 2,2 ,4)4'f5,5 -hexaCB 2,2 I3l4l4 l5,5 -heptaCB (#138) (#153) (#180) CO O CO X i in uf CO *J*n> o oi o co~ m o CO *-< c 0) Q. CO co" CQ CQ. O 2 "c _ 10 O o. o O CO CO co" O O CM o CM" CO CO" CM" O O 10 O O 10" O O CO O O CM" O O iO_ o. o O Tt O O O CO co" CM CM" O O Cly Clx ^^^__> JP450 X protein, Arene oxide Phenols intermediate —————>• Macromolecular RNA, DMA adducts epoxide Glutathione hydrolase S-transferases ; * Dihydrodiols Glutathione conjugates dehydrogenase multiple pathways Catechols Methyl sulfonyl metabolites Phenol conjugates c. °,H c. SOCH3 2,2',4-triCB 3,2',4',5-tetrachloro- 4,4'-bis(methylsulfonyl)- 2,4,6-tetrachloro- 4-biphenylol 2,21,5,51-tetraCB 4'-biphenylol